Method of treating viral infections

ABSTRACT

In one aspect, a method of treating a disorder associated with chronic inflammation includes administering to an individual in need thereof a therapeutically effective amount of isomyosmine or a pharmaceutically acceptable salt thereof. In some aspects, the disorder is a cancer, an autoimmune disorder, hypertension, or autism. In other aspects, isomyosmine is administered to treat viral infections or disorders associated with elevated levels of hydrogen peroxide and/or other Reactive Oxygen Species (ROS).

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 15/558,094,filed Sep. 13, 2017, which is a U.S. National Phase of PCT/US16/25126,filed Mar. 31, 2016, which claims priority to U.S. provisionalapplication No. 62/140,618, filed Mar. 31, 2015, the disclosure of whichis hereby incorporated by reference in its entirety.

SUMMARY

In one aspect, a method of treating a cancer comprises administering toan individual in need thereof a pharmaceutical composition containing atherapeutically effective amount of isomyosmine or a pharmaceuticallyacceptable salt thereof. Aspects of treating cancers may involve themodification of a tumor microenvironment. It is believed thatisomyosmine blocks the production or otherwise reduces the concentrationof hydrogen peroxide and/or other Reactive Oxygen Species (ROS) in themicroenvironment, which in turn may help restore normal function ofendogenous species. Modification of the tumor microenvironment also mayimprove the efficacy other cancer therapies, e.g., chemotherapies. Tothe extent that the presence of hydrogen peroxide and/or other ROS maybe responsible for oncogenesis, isomyosmine may also be effective forpreventing or delaying the onset of a tumor.

In another aspect, a method of treating an autoimmune disorder comprisesadministering to an individual in need thereof a pharmaceuticalcomposition containing a therapeutically effective amount of isomyosmineor a pharmaceutically acceptable salt thereof.

In another aspect, a method of treating autism comprises administeringto an individual in need thereof a pharmaceutical composition containinga therapeutically effective amount of isomyosmine or a pharmaceuticallyacceptable salt thereof.

In another aspect, a method of treating a viral infection comprisesadministering to an individual in need thereof a pharmaceuticalcomposition containing a therapeutically effective amount of isomyosmineor a pharmaceutically acceptable salt thereof. In one example, the virusis human immunodeficiency virus (HIV). In another example, the virus ishuman papillomavirus (HPV).

In another aspect, a method of treating hypertension or high bloodpressure comprises administering to an individual in need thereof apharmaceutical composition containing a therapeutically effective amountof isomyosmine or a pharmaceutically acceptable salt thereof.

In some aspects, a method of treating a disorder associated with chronicinflammation comprises administering to an individual in need thereof apharmaceutical composition containing a therapeutically effective amountof isomyosmine or a pharmaceutically acceptable salt thereof.

In other aspects, a method of treating a disorder associated withincreased levels of hydrogen peroxide and/or other ROS comprisesadministering to an individual in need thereof a pharmaceuticalcomposition containing a therapeutically effective amount of isomyosmineor a pharmaceutically acceptable salt thereof. It is postulated thatisomyosmine inhibits the production of hydrogen peroxide, eitherdirectly or indirectly, e.g., by inhibiting enzymes, such as monoamineoxidase, that produce hydrogen peroxide and/or other ROS. Disordersassociated with increased levels of hydrogen peroxide and/or other ROSmay include cancers, autoimmune disorders, and the like, includingspecific cancers and autoimmune disorders mentioned herein as well asother conditions which can be determined to be associated with elevatedlevels of hydrogen peroxide (and/or other ROS) with the aid of no morethan routine experimentation.

In yet another aspect, a method of treating a disorder associated withabnormal expression or activity of dual-specificity tyrosinephosphorylation-regulated kinase 1A (DYRK1A) comprises administering toan individual in need thereof a pharmaceutical composition containing atherapeutically effective amount of isomyosmine or a pharmaceuticallyacceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention and certainadvantages thereof may be acquired by referring to the followingdetailed description in consideration with the accompanying drawings, inwhich:

FIG. 1 is a graph showing the ability of isomyosmine, myosmine,anatabine, anabasine, and nomicotine to inhibit the enzymatic activityof MAO-A.

FIG. 2 is a graph showing the ability of isomyosmine, myosmine,anatabine, anabasine, and nomicotine to inhibit the activity of MAO-B.

DETAILED DESCRIPTION

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. As used herein, the term “pharmaceutically acceptable”means any molecular entity or composition that does not produce anadverse, allergic or other untoward or unwanted reaction whenadministered to an individual. As used herein, the term“pharmaceutically acceptable composition” is synonymous with“pharmaceutical composition” and means a therapeutically effectiveconcentration of an active ingredient, such as, e.g., any of thetherapeutic compounds disclosed herein. A pharmaceutical compositiondisclosed herein is useful for medical and veterinary applications. Apharmaceutical composition may be administered to an individual alone,or in combination with other supplementary active ingredients, agents,drugs or hormones.

A pharmaceutical composition disclosed herein may include apharmaceutically acceptable carrier that facilitates processing of anactive ingredient into pharmaceutically acceptable compositions. As usedherein, the term “pharmacologically acceptable carrier” is synonymouswith “pharmacological carrier” and means any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary” or“excipient.” Such a carrier generally is mixed with an active compoundor permitted to dilute or enclose the active compound and can be asolid, semi-solid, or liquid agent. It is understood that the activeingredients can be soluble or can be delivered as a suspension in thedesired carrier or diluent. Any of a variety of pharmaceuticallyacceptable carriers can be used including, without limitation, aqueousmedia such as, e.g., water, saline, glycine, hyaluronic acid and thelike; solid carriers such as, e.g., mannitol, lactose, starch, magnesiumstearate, sodium saccharin, talcum, cellulose, glucose, sucrose,magnesium carbonate, and the like; solvents; dispersion media; coatings;antibacterial and antifungal agents; isotonic and absorption delayingagents; or any other inactive ingredient. Selection of apharmacologically acceptable carrier can depend on the mode ofadministration. Except insofar as any pharmacologically acceptablecarrier is incompatible with the active ingredient, its use inpharmaceutically acceptable compositions is contemplated. Non-limitingexamples of specific uses of such pharmaceutical carriers can be foundin Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C.Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed.1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R.Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman &Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman etal., eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook ofPharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications,4th edition 2003). These protocols are routine procedures and anymodifications are well within the scope of one skilled in the art andfrom the teaching herein.

Isomyosmine

A pharmaceutical composition may contain isomyosmine. Isomyosmine(3-(3,4-dihydro-2H-pyrrol-2-yl)-pyridine) is a nicotine related alkaloidpresent in solanecea plants containing nicotine.

Isomyosmine may be prepared synthetically using known techniques, andalso is commercially available from several chemical suppliers.Isomyosmine has two optical isomers (+/−) owing to an asymmetric carbonatom within its pyrrole ring that joins to the pyridine ring. Unlessotherwise clear from context, the term “isomyosmine,” as used herein, isinclusive of enantiomeric mixtures (+/−) including racemic mixtures, aswell as isolated forms of one or the other enantiomer.

Unless otherwise clear from context, “isomyosmine” as used herein refersto both salt and non-salt forms of isomyosmine. Non-limiting examples ofpossible salts are described in P. H. Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection and Use,Weinheim/Zürich:Wiley-VCHNHCA, 2002, including salts of1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid(L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoricacid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid),caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconicacid (D), glucuronic acid (D), glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid,lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid(DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid,oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionicacid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid,toluenesulfonic acid (p), and undecylenic acid.

As an alternative to preparing isomyosmine synthetically, isomyosminecan be obtained by extraction from tobacco or other sources in which itoccurs naturally. For example, a tobacco extract may be prepared fromcured tobacco stems, lamina, or both. In the extraction process, curedtobacco material is extracted with a solvent, typically water, ethanol,steam, or carbon dioxide. The resulting solution contains the solublecomponents of the tobacco, including isomyosmine. Isomyosmine may bepurified from the other components of the tobacco using suitabletechniques such as liquid chromatography.

In pharmaceutical applications, an isolated form of isomyosminegenerally is used. An “isolated form of isomyosmine,” as used herein,refers to isomyosmine that either has been prepared synthetically or hasbeen substantially separated from natural materials in which it occurs.The isolated form of isomyosmine should have a very high purity(including enantiomeric purity in the case where an enantiomer is used).In the case of synthetic isomyosmine, for example, purity refers to theratio of the weight of isomyosmine to the weight of the end reactionproduct. In the case of isolating isomyosmine from native material, forexample, purity refers to the ratio of the weight of isomyosmine to thetotal weight of the isomyosmine-containing extract. Usually, the levelof purity is at least about 95%, more usually at least about 96%, about97%, about 98%, or higher. For example, the level of purity may be about98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%,99.9%, or higher.

While not wanting to be bound by theory, it is believed that isomyosminehas a unique ability to affect basic cell function and directly and/orindirectly inhibit the production of Reactive Oxygen Species (ROS),particularly hydrogen peroxide (H202). Cells typically havemitochondria, which is prone to breaking down to form H202. In someaspects, isomyosmine is believed to help restore mitochondria functionor, stated differently, treat mitochondria dysfunction. Isomyosmine isan inhibitor of monoamine oxidase (including MAO-A and MAO-B), an enzymethat catalyzes the production of hydrogen peroxide.

Isomyosmine is also believed to regulate dual-specificity tyrosinephosphorylation-regulated kinase 1A (DYRK1A). DYRK1A plays a role inregulating the body's immune response as well as in viral replication.Abnormal expression or activity of DYRK1A also has been associated withneuropsychiatric disorders including Down's syndrome and Alzheimer'sdisease. Owing to its ability to regulate DYRK1A, isomyosmine may beeffective in treating a wide variety of disorders ranging from cancersto viral infections and high blood pressure.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, sweetening orflavoring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, citratebuffers, phosphate buffers, neutral buffered saline, phosphate bufferedsaline and borate buffers. It is understood that acids or bases can beused to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition and chelants, such as, e.g., DTPA orDTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustorsuseful in a pharmaceutical composition include, without limitation,salts such as, e.g., sodium chloride, potassium chloride, mannitol orglycerin and other pharmaceutically acceptable tonicity adjustor. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

In one embodiment, a pharmaceutical composition comprises isomyosmineand a pharmaceutically acceptable adjuvant. In another embodiment, apharmaceutical composition disclosed herein comprises isomyosmine, apharmaceutically acceptable solvent, and a pharmaceutically acceptableadjuvant. In aspects of this embodiment, a pharmaceutical compositiondisclosed herein may further comprise a pharmaceutically acceptablestabilizing agent. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may further comprise a pharmaceuticallyacceptable carrier, a pharmaceutically acceptable component, or bothpharmaceutically acceptable carrier and pharmaceutically acceptablecomponent.

Compositions may contain isomyosmine, alone or with other therapeuticcompound(s). A therapeutic compound is a compound that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. A therapeuticcompound disclosed herein may be used in the form of a pharmaceuticallyacceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride.Additionally, therapeutic compound disclosed herein may be provided asracemates, or as individual enantiomers, including the R- orS-enantiomer. Thus, the therapeutic compound disclosed herein maycomprise a R-enantiomer only, a S-enantiomer only, or a combination ofboth a R-enantiomer and a S-enantiomer of a therapeutic compound. Insome aspects, the therapeutic compound may have anti-inflammatoryactivity.

References herein to “therapeutic compound” may refer to isomyosmine, anactive compound other than isomyosmine as described herein, or both.

In an embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of reducing the levels of aninflammation-inducing molecule. In an aspect of this embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activitycapable of reducing the levels of substance P(SP), calcitoningene-related peptide (CGRP), glutamate, or a combination thereof. Inother aspects of this embodiment, a therapeutic compound disclosedherein has an anti-inflammatory activity capable of reducing the levelsof SP, CGRP, glutamate, or a combination thereof released from a sensoryneuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In yet otheraspects of this embodiment, a therapeutic compound disclosed herein hasan anti-inflammatory activity capable of reducing the levels of SP,CGRP, glutamate, or a combination thereof released from a sensory neuronin a range from, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

Prostaglandins mediate a local inflammatory response and are involved inall inflammatory functions through action on prostaglandin receptors andmediate inflammatory signaling including chemotaxis (macrophages,neutrophils and eosinophils), vasodilation and algesia. However, thePG-mediated inflammatory response is self-limiting (resolving). Theprinciple resolution factor is a prostaglandin called 15dPGJ2, which isan endogenous agonist of peroxisome proliferator-activator receptorgamma (PPAR-γ) signaling. PPAR-γ signaling pathway 1) induces apoptosisof macrophage M1 cells, thereby reducing the levels of Th1pro-inflammatory cytokines and 2) promotes differentiation of monocytesinto macrophage M2 cells. Macrophage M2 cells produce and release Th2anti-inflammatory cytokines.

In an embodiment, a therapeutic compound has an anti-inflammatoryactivity capable of reducing the levels of an inflammation inducingprostaglandin. In other aspects of this embodiment, a therapeuticcompound has an anti-inflammatory activity capable of reducing thelevels of an inflammation inducing prostaglandin released from a sensoryneuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In yet otheraspects of this embodiment, a therapeutic compound has ananti-inflammatory activity capable of reducing the levels of aninflammation inducing prostaglandin released from a sensory neuron in arange from, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In another embodiment, a therapeutic compound has an anti-inflammatoryactivity substantially similar to 15dPGJ2. In aspects of thisembodiment, a therapeutic compound has an anti-inflammatory activitythat is, e.g., at least 5%, at least 15%, at least 25%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95% of the activityobserved for 15dPGJ2. In other aspects of this embodiment, a therapeuticcompound has an anti-inflammatory activity that is in a range from,e.g., about 5% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100%, about 25%to about 90%, about 50% to about 90%, about 60% to about 90%, about 70%to about 90%, about 80% to about 90%, about 25% to about 80%, about 50%to about 80%, about 60% to about 80%, about 70% to about 80%, about 25%to about 70%, about 50% to about 70%, about 25% to about 60%, about 50%to about 60%, or about 25% to about 50% of the activity observed for15dPGJ2.

The peroxisome proliferator-activated receptors (PPARs) are a group ofnuclear receptor proteins that function as transcription factorsregulating the expression of genes. All PPARs are known toheterodimerize with the retinoid X receptor (RXR) and bind to specificregions on the DNA of target genes called peroxisome proliferatorhormone response elements (PPREs). PPARs play essential roles in theregulation of cellular differentiation, development, and metabolism(carbohydrate, lipid, protein), and tumorigenesis of higher organisms.The family comprises three members, PPAR-α, PPAR-γ, and PPAR-δ (alsoknown as PPAR-β). PPAR-α is expressed in liver, kidney, heart, muscle,adipose tissue, as well as other tissues. PPAR-δ is expressed in manytissues but markedly in brain, adipose tissue, and skin. PPAR-γcomprises three alternatively-spliced forms, each with a differentexpression pattern. PPAR-γ1 is expressed in virtually all tissues,including heart, muscle, colon, kidney, pancreas, and spleen. PPAR-γ2 isexpressed mainly in adipose tissue. PPAR-γ3 is expressed in macrophages,large intestine, and white adipose tissue. Endogenous ligands for thePPARs include free fatty acids and eicosanoids. PPAR-γ is activated byPGJ2 (a prostaglandin), whereas PPAR-α is activated by leukotriene B4.

In some aspects, a therapeutic compound may have an anti-inflammatoryactivity capable of stimulating some or all PPAR signaling pathways. Itis contemplated that such a therapeutic compound therefore may act as aPPAR pan-agonist or possibly as a selective PPAR agonist.

In other aspects, a therapeutic compound has an anti-inflammatoryactivity capable of stimulating a PPAR-α signaling pathway. In aspectsof this embodiment, a therapeutic compound disclosed herein stimulates aPPAR-α signaling pathway by, e.g., at least 5%, at least 15%, at least25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least90%. In other aspects of this embodiment, a therapeutic compounddisclosed herein stimulates a PPAR-α signaling pathway in a range from,e.g., about 5% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100%, about 25%to about 90%, about 50% to about 90%, about 60% to about 90%, about 70%to about 90%, about 80% to about 90%, about 25% to about 80%, about 50%to about 80%, about 60% to about 80%, about 70% to about 80%, about 25%to about 70%, about 50% to about 70%, about 25% to about 60%, about 50%to about 60%, or about 25% to about 50%.

In some aspects, a therapeutic compound has an anti-inflammatoryactivity capable of stimulating a PPAR-6 signaling pathway. Atherapeutic compound may, for example, stimulate a PPAR-6 signalingpathway by at least 5%, at least 15%, at least 25%, at least 50%, atleast 60%, at least 70%, at least 80%, or at least 90%. In some cases, atherapeutic compound stimulates a PPAR-6 signaling pathway in a rangefrom, e.g., about 5% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about25% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 80% to about 90%, about 25% to about 80%, about50% to about 80%, about 60% to about 80%, about 70% to about 80%, about25% to about 70%, about 50% to about 70%, about 25% to about 60%, about50% to about 60%, or about 25% to about 50%.

In some aspects, a therapeutic compound has an anti-inflammatoryactivity capable of stimulating a PPAR-γ signaling pathway. Atherapeutic compound may be capable of binding to all isoforms ofPPAR-γ, or may be capable of selectively binding to either PPAR-γ1,PPAR-γ2, PPAR-γ3, or any combination of two thereof. A therapeuticcompound may stimulate a PPAR-γ signaling pathway by, e.g., at least 5%,at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, atleast 80%, or at least 90%. A therapeutic compound may stimulate aPPAR-γ signaling pathway in a range from, e.g., about 5% to about 100%,about 50% to about 100%, about 60% to about 100%, about 70% to about100%, about 80% to about 100%, about 25% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 80% toabout 90%, about 25% to about 80%, about 50% to about 80%, about 60% toabout 80%, about 70% to about 80%, about 25% to about 70%, about 50% toabout 70%, about 25% to about 60%, about 50% to about 60%, or about 25%to about 50%.

Macrophages are activated and polarized into distinct phenotypesexpressing unique cell surface molecules and secreting discrete sets ofcytokines and chemokines. The classical M1 phenotype supportspro-inflammatory Th1 responses driven by cytokines such as, e.g.,Interleukin-6 (IL-6), IL-12 and IL-23, while the alternate M2 phenotypeis generally supportive of anti-inflammatory processes driven by IL-10.M2 cells can be further classified into subsets, M2a, M2b, and M2c,based on the type of stimulation and the subsequent expression ofsurface molecules and cytokines.

In yet another embodiment, a therapeutic compound has ananti-inflammatory activity capable of promoting the resolving phenotypicchange of M1 to M2. A therapeutic compound may have an anti-inflammatoryactivity capable of inducing apoptosis of macrophage M1 cells. Atherapeutic compound may have an anti-inflammatory activity capable ofpromoting differentiation of macrophage M2 cells. In yet another aspectof this embodiment, a therapeutic compound disclosed herein has ananti-inflammatory activity capable of inducing apoptosis of macrophageM1 cells and promoting differentiation of macrophage M2 cells.

In still another embodiment, a therapeutic compound has ananti-inflammatory activity capable of modulating Th1 and Th2 cytokines.A therapeutic compound may have an anti-inflammatory activity capable ofreducing the levels of Interferon-gamma (IFN-γ), tumor necrosisfactor-alpha (TNF-α), interleukin-12 (IL-12), or a combination thereofreleased from a Th1 cell. In other aspects of this embodiment, atherapeutic compound may have an anti-inflammatory activity capable ofreducing the levels of IFN-γ, TNF-α, IL-12, or a combination thereofreleased from a Th1 cell by, e.g., at least 10%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least80%, or at least 90%. In yet other aspects of this embodiment, atherapeutic compound may have an anti-inflammatory activity capable ofreducing the levels of IFN-γ, TNF-α, IL-12, or a combination thereofreleased from a Th1 cell in a range from, e.g., about 5% to about 100%,about 10% to about 100%, about 20% to about 100%, about 30% to about100%, about 40% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100%, about 10%to about 90%, about 20% to about 90%, about 30% to about 90%, about 40%to about 90%, about 50% to about 90%, about 60% to about 90%, about 70%to about 90%, about 10% to about 80%, about 20% to about 80%, about 30%to about 80%, about 40% to about 80%, about 50% to about 80%, or about60% to about 80%, about 10% to about 70%, about 20% to about 70%, about30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another aspect of this embodiment, a therapeutic compound has ananti-inflammatory activity capable of increasing the levels of IL-10released from a Th2 cell. A therapeutic compound may have ananti-inflammatory activity capable of increasing the levels of IL-10released from a Th2 cell by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In yet other aspects of this embodiment, a therapeutic compound mayhave an anti-inflammatory activity capable of increasing the levels ofIL-10 released from a Th2 cell in a range from, e.g., about 5% to about100%, about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about10% to about 90%, about 20% to about 90%, about 30% to about 90%, about40% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 10% to about 80%, about 20% to about 80%, about30% to about 80%, about 40% to about 80%, about 50% to about 80%, orabout 60% to about 80%, about 10% to about 70%, about 20% to about 70%,about 30% to about 70%, about 40% to about 70%, or about 50% to about70%.

In another aspect of this embodiment, a therapeutic compound has ananti-inflammatory activity capable of reducing the levels of IFN-γ,TNF-α, IL-12, or a combination thereof released from a Th1 cell andincreasing the levels of IL-10 released from a Th2 cell. A therapeuticcompound may have an anti-inflammatory activity capable of reducing thelevels of IFN-γ, TNF-α, IL-12, or a combination thereof released from aTh1 cell by, e.g., at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90% or at least 95%, andcapable of increasing the levels of IL-10 released from a Th2 cell by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In yet other aspects ofthis embodiment, a therapeutic compound may have an anti-inflammatoryactivity capable of reducing the levels of IFN-γ, TNF-α, IL-12, or acombination thereof released from a Th1 cell in a range from, e.g.,about 5% to about 100%, about 10% to about 100%, about 20% to about100%, about 30% to about 100%, about 40% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 10% to about 90%, about 20% to about 90%, about 30%to about 90%, about 40% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 10% to about 80%, about 20%to about 80%, about 30% to about 80%, about 40% to about 80%, about 50%to about 80%, or about 60% to about 80%, about 10% to about 70%, about20% to about 70%, about 30% to about 70%, about 40% to about 70%, orabout 50% to about 70%, and capable of increasing the levels of IL-10released from a Th2 cell in a range from, e.g., about 10% to about 100%,about 20% to about 100%, about 30% to about 100%, about 40% to about100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 100%, about 80% to about 100%, about 10% to about 90%, about 20%to about 90%, about 30% to about 90%, about 40% to about 90%, about 50%to about 90%, about 60% to about 90%, about 70% to about 90%, about 10%to about 80%, about 20% to about 80%, about 30% to about 80%, about 40%to about 80%, about 50% to about 80%, or about 60% to about 80%, about10% to about 70%, about 20% to about 70%, about 30% to about 70%, about40% to about 70%, or about 50% to about 70%.

In addition to isomyosmine, pharmaceutical formulations as describedherein may include additional therapeutic compound(s) such as anon-steroidal anti-inflammatory drug (NSAID). NSAIDs are a large groupof therapeutic compounds with analgesic, anti-inflammatory, andanti-pyretic properties. NSAIDs reduce inflammation by blockingcyclooxygenase. NSAIDs include, without limitation, aceclofenac,acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin,aminophenazone, antraphenine, aspirin, azapropazone, benorilate,benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin,choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal,emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac,fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethylsalicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac,lactyl phenetidin, loxoprofen, lumiracoxib, mefenamic acid, meloxicam,metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone,naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone,pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib,salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine,tolfenamic acid, valdecoxib, and zomepirac.

NSAIDs may be classified based on their chemical structure or mechanismof action. Non-limiting examples of NSAIDs include a salicylatederivative NSAID, a p-amino phenol derivative NSAID, a propionic acidderivative NSAID, an acetic acid derivative NSAID, an enolic acidderivative NSAID, a fenamic acid derivative NSAID, a non-selectivecyclooxygenase (COX) inhibitor, a selective cyclooxygenase-1 (COX-1)inhibitor, and a selective cyclooxygenase-2 (COX-2) inhibitor. An NSAIDmay be a profen. Examples of a suitable salicylate derivative NSAIDinclude, without limitation, acetylsalicylic acid (aspirin), diflunisal,and salsalate. Examples of a suitable p-amino phenol derivative NSAIDinclude, without limitation, paracetamol and phenacetin. Examples of asuitable propionic acid derivative NSAID include, without limitation,alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin,pranoprofen, and suprofen. Examples of a suitable acetic acid derivativeNSAID include, without limitation, aceclofenac, acemetacin, actarit,alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac,fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac,nabumetone, naproxen, oxametacin, sulindac, and zomepirac. Examples of asuitable enolic acid (oxicam) derivative NSAID include, withoutlimitation, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, andtenoxicam. Examples of a suitable fenamic acid derivative NSAID include,without limitation, flufenamic acid, mefenamic acid, meclofenamic acid,and tolfenamic acid. Examples of a suitable selective COX-2 inhibitorsinclude, without limitation, celecoxib, etoricoxib, firocoxib,lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

A therapeutic compound may have a log P value indicating that thecompound is soluble in an organic solvent. As used herein, the term “logvalue” refers to the logarithm (base 10) of the partition coefficient(P) for a compound and is a measure of lipophilicity. Typically, P isdefined as the ratio of concentrations of a unionized compound in thetwo phases of a mixture of two immiscible solvents at equilibrium. Thus,log P=Log 10 (P), where P=[solute in immiscible solvent 1]/[solute inimmiscible solvent 2]. With regard to organic and aqueous phases, thelog P value of a compound is constant for any given pair of aqueous andorganic solvents, and its value can be determined empirically by one ofseveral phase-partitioning methods known to one skilled in the artincluding, e.g., a shake flask assay, a HPLC assay, and an interfacebetween two immiscible electrolyte solutions (ITIES) assay.

In aspects of this embodiment, a therapeutic compound may have a log Pvalue indicating that the compound is substantially soluble in anorganic solvent. In aspects of this embodiment, a therapeutic compounddisclosed herein may have a log P value indicating that the compound is,e.g., at least 50% soluble in an organic solvent, at least 60% solublein an organic solvent, at least 70% soluble in an organic solvent, atleast 80% soluble in an organic solvent, or at least 90% soluble in anorganic solvent. In aspects of this embodiment, a therapeutic compounddisclosed herein may have a log P value indicating that the compound isbetween, e.g., about 50% to about 100% soluble in an organic solvent,about 60% to about 100% soluble in an organic solvent, about 70% toabout 100% soluble in an organic solvent, about 80% to about 100%soluble in an organic solvent, or about 90% to about 100% soluble in anorganic solvent.

In aspects of this embodiment, a therapeutic compound disclosed hereinmay have a log P value of, e.g., more than 1.1, more than 1.2, more than1.4, more than 1.6, more than 1.8, more than 2.0, more than 2.2, morethan 2.4, more than 2.6, more than 2.8, more than 3.0, more than 3.2,more than 3.4, or more than 3.6. In other aspects of this embodiment, atherapeutic compound disclosed herein may have a log P value in therange of, e.g., between 1.8 and 4.0, between 2.0 and 4.0, between 2.1and 4.0, between 2.2 and 4.0, or between 2.3 and 4.0, between 2.4 and4.0, between 2.5 and 4.0, between 2.6 and 4.0, or between 2.8 and 4.0.In other aspects of this embodiment, a therapeutic compound disclosedherein may have a log P value in the range of, e.g., between 3.0 and4.0, or between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 and 4.0,between 3.4 and 4.0, between 3.5 and 4.0, or between 3.6 and 4.0. Instill other aspects of this embodiment, a therapeutic compound disclosedherein may have a log P value in the range of, e.g., between 2.0 and2.5, between 2.0 and 2.7, between 2.0 and 3.0, or between 2.2 and 2.5.

A therapeutic compound may have a polar surface area that ishydrophobic. As used herein, the term “polar surface area” refers to thesurface sum over all of the polar atoms in the structure of a compoundand is a measure of hydrophobicity. Typically, these polar atomsinclude, e.g., oxygen, nitrogen, and their attached hydrogens. Inaspects of this embodiment, a therapeutic compound disclosed herein mayhave a polar surface area of, e.g., less than 8.0 nm², less than 7.0nm², less than 6.0 nm², less than 5.0 nm², less than 4.0 nm², or lessthan 3.0 nm².

In some aspects, a therapeutic compound may be a PPAR-γ agonist.Examples of a suitable PPAR-γ agonist include, without limitation,benzbromarone, a cannabidiol, cilostazol, curcumin,delta(9)-tetrahydrocannabinol, glycyrrhetinic acid, indomethacin,irbesartan, monascin, mycophenolic acid, resveratrol, 6-shogaol,telmisartan, a thiazolidinedione like rosiglitazone, pioglitazone, andtroglitazone, a NSAID, and a fibrate. Other suitable PPAR-γ agonists aredescribed in Masson et al. US 2011/0195993 Al, the disclosure of whichis hereby incorporated by reference.

A therapeutic compound may be a nuclear receptor binding agent. Examplesof a suitable nuclear receptor binding agent include, withoutlimitation, a retinoic acid receptor (RAR) binding agent, a retinoid Xreceptor (RXR) binding agent, a liver X receptor (LXR) binding agent anda vitamin D binding agent.

A therapeutic compound may be an anti-hyperlipidemic agent. There areseveral classes of anti-hyperlipidemic agents (also known ashypolipidemic agents). They may differ in both their impact on thecholesterol profile and adverse effects. For example, some may lower lowdensity lipoprotein (LDL), while others may preferentially increase highdensity lipoprotein (HDL). Clinically, the choice of an agent willdepend on the cholesterol profile of an individual, cardiovascular riskof an individual, and/or the liver and kidney functions of anindividual. Examples of a suitable anti-hyperlipidemic agent include,without limitation, a fibrate, a statin, a tocotrienol, a niacin, a bileacid sequestrants (resin), a cholesterol absorption inhibitor, apancreatic lipase inhibitor, and a sympathomimetic amine.

A therapeutic compound may be a fibrate. Fibrates are a class ofamphipathic carboxylic acids with lipid level modifying properties.These therapeutic compounds are used for a range of metabolic disorders.One non-limiting use is as an anti-hyperlipidemic agent where it maylower levels of, e.g., triglycerides and LDL as well as increase levelsof HDL. Examples of a suitable fibrate include, without limitation,bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and fenofibrate.

A therapeutic compound may be a statin. Statins (or HMG-CoA reductaseinhibitors) are a class of therapeutic compounds used to lower LDLand/or cholesterol levels by inhibiting the enzyme HMG-CoA reductase,which plays a central role in the production of cholesterol in theliver. To compensate for the decreased cholesterol availability,synthesis of hepatic LDL receptors is increased, resulting in anincreased clearance of LDL particles from the blood. Examples of asuitable statin include, without limitation, atorvastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

A therapeutic compound may be a tocotrienol. Tocotrienols are anotherclass of HMG-CoA reductase inhibitors and may be used to lower LDLand/or cholesterol levels by inducing hepatic LDL receptor up-regulationand/or decreasing plasma LDL levels. Examples of a suitable tocotrienolinclude, without limitation, a γ-tocotrienol and a δ-tocotrienol.

A therapeutic compound may be a niacin. Niacins are a class oftherapeutic compounds with lipid level modifying properties. Forexample, a niacin may lower LDL by selectively inhibiting hepaticdiacyglycerol acyltransferase 2, reduce triglyceride synthesis, and VLDLsecretion through a receptor HM74 and HM74A or GPR109A. Thesetherapeutic compounds are used for a range of metabolic disorders. Onenon-limiting use is as an anti-hyperlipidemic agent where it may inhibitthe breakdown of fats in adipose tissue. Because a niacin blocks thebreakdown of fats, it causes a decrease in free fatty acids in the bloodand, as a consequence, decreases the secretion of very-low-densitylipoproteins (VLDL) and cholesterol by the liver. By lowering VLDLlevels, a niacin may also increase the level of HDL in blood. Examplesof a niacin include, without limitation, acipimox, niacin, nicotinamide,and vitamin B3.

A therapeutic compound may be a bile acid sequestrant. Bile acidsequestrants (also known as resins) are a class of therapeutic compoundsused to bind certain components of bile in the gastrointestinal tract.They disrupt the enterohepatic circulation of bile acids by sequesteringthem and preventing their reabsorption from the gut. Bile acidsequestrants are particularly effective for lowering LDL and cholesterolby sequestering the cholesterol-containing bile acids released into theintestine and preventing their reabsorption from the intestine. Inaddition, a bile acid sequestrant may also raise HDL levels. Examples ofa suitable bile acid sequestrant include, without limitation,cholestyramine, colesevelam, and colestipol.

In some aspects, a therapeutic compound may be a cholesterol absorptioninhibitor. Cholesterol absorption inhibitors are a class of therapeuticcompounds that inhibits the absorption of cholesterol from theintestine. Decreased cholesterol absorption leads to an up-regulation ofLDL-receptors on the surface of cells and an increased LDL-cholesteroluptake into these cells, thus decreasing levels of LDL in the bloodplasma. Examples of a suitable cholesterol absorption inhibitor include,without limitation, ezetimibe, a phytosterol, a sterol and a stanol.

A therapeutic compound may be a fat absorption inhibitor. Fat absorptioninhibitors are a class of therapeutic compounds that inhibits theabsorption of fat from the intestine. Decreased fat absorption reducescaloric intake. In one aspect, a fat absorption inhibitor inhibitspancreatic lipase, an enzyme that breaks down triglycerides in theintestine. Examples of a suitable fat absorption inhibitor include,without limitation, orlistat.

A therapeutic compound may be a sympathomimetic amine. Sympathomimeticamines are a class of therapeutic compounds that mimic the effects oftransmitter substances of the sympathetic nervous system such ascatecholamines, epinephrine (adrenaline), norepinephrine(noradrenaline), and/or dopamine. A sympathomimetic amine may act as anα-adrenergic agonist, a β-adrenergic agonist, a dopaminergic agonist, amonoamine oxidase (MAO) inhibitor, and a COMT inhibitor. Suchtherapeutic compounds, among other things, are used to treat cardiacarrest, low blood pressure, or even delay premature labor. Examples of asuitable sympathomimetic amine include, without limitation, clenbuterol,salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine,phenylephrine, isoproterenol, dobutamine, methylphenidate,lisdexamfetamine, cathine, cathinone, methcathinone, cocaine,benzylpiperazine (BZP), methylenedioxypyrovalerone (MDPV),4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine.

In another aspect, isomyosmine may be administered for treating tobaccoor other substance addiction, including promoting smoking cessation orotherwise assisting individuals in reducing or eliminating cravings fornicotine or dependence on nicotine. Isomyosmine was found to be a potentinhibitor of monoamine oxidase (MAO), including both MAO-A and MAO-B.Through these and/or other mechanisms, including one or more of theaforementioned anti-inflammatory mechanisms, pharmaceutical compositionscontaining isomyosmine may be particularly effective for treatingtobacco addiction and/or for assisting individuals in reducing oreliminating cravings for nicotine or dependence on nicotine. For someindividuals, the administration of isomyosmine may be effective fortreating more than one disorder. For example, COPD is a relativelycommon disorder among smokers. Compositions containing isomyosmine maybe useful for assisting such individuals not only with smokingcessation, but also in the treatment of COPD and/or other chronicinflammation-related disorders suffered by the individual, whether ornot caused by or related to smoking.

A therapeutic compound disclosed herein may be an ester of a therapeuticcompound. In general, an ester of a therapeutic compound increases thelog P value relative to the same therapeutic compound without the estermodification. An ester group may be attached to a therapeutic compoundby, e.g., a carboxylic acid or hydroxyl functional group present of thetherapeutic compound. An ester of a therapeutic compound may have anincreased hydrophobicity, and as such, may be dissolved in a reducedvolume of solvent disclosed herein. In some instances, an ester of atherapeutic compound may be combined directly with an adjuvant disclosedherein, thereby eliminating the need of a solvent. An ester of atherapeutic compound may enable the making of a pharmaceuticalcomposition disclosed herein, in situations where a non-esterified formof the same therapeutic compound is otherwise immiscible in a solventdisclosed herein. An ester of a therapeutic compound may still bedelivered in a manner that more effectively inhibits a pro-inflammatoryresponse as long as the compound is combined with an adjuvant disclosedherein. In one embodiment, a therapeutic compound may be reacted withethyl ester in order to form an ethyl ester of the therapeutic compound.

In another embodiment, a pharmaceutical composition does not comprise apharmaceutically acceptable solvent as previously described. In anaspect of this embodiment, a pharmaceutical composition may comprise atherapeutic compound and a pharmaceutically acceptable adjuvant butwithout a pharmaceutically acceptable solvent.

A pharmaceutical composition may comprise a therapeutic compound in anamount sufficient to allow customary administration to an individual. Inaspects of this embodiment, a pharmaceutical composition disclosedherein may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, atleast 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, atleast 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeuticcompound. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may be, e.g., at least 5 mg, at least 10mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, atleast 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, atleast 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, atleast 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg,at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of atherapeutic compound. In yet other aspects of this embodiment, apharmaceutical composition disclosed herein may be in the range of,e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg,about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mgto about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg toabout 1,500 mg. In still other aspects of this embodiment, apharmaceutical composition disclosed herein may be in the range of,e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg,about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mgto about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg,about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg toabout 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000mg, or about 5 mg to about 250 mg.

Pharmaceutical compositions as described herein may include apharmaceutically acceptable solvent. A solvent is a liquid, solid, orgas that dissolves another solid, liquid, or gaseous (the solute),resulting in a solution. Solvents useful in the pharmaceuticalcompositions include, without limitation, a pharmaceutically acceptablepolar aprotic solvent, a pharmaceutically acceptable polar proticsolvent and a pharmaceutically acceptable non-polar solvent. Apharmaceutically acceptable polar aprotic solvent includes, withoutlimitation, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate,acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO). A pharmaceutically acceptable polar protic solventincludes, without limitation, acetic acid, formic acid, ethanol,n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol,n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water.A pharmaceutically acceptable non-polar solvent includes, withoutlimitation, pentane, cyclopentane, hexane, cyclohexane, benzene,toluene, 1,4-dioxane, chloroform, n-methyl-pyrrilidone (NMP), anddiethyl ether.

A pharmaceutical composition disclosed herein may comprise a solvent inan amount sufficient to dissolve a therapeutic compound disclosedherein. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein may comprise a solvent in an amount of,e.g., less than about 90% (v/v), less than about 80% (v/v), less thanabout 70% (v/v), less than about 65% (v/v), less than about 60% (v/v),less than about 55% (v/v), less than about 50% (v/v), less than about45% (v/v), less than about 40% (v/v), less than about 35% (v/v), lessthan about 30% (v/v), less than about 25% (v/v), less than about 20%(v/v), less than about 15% (v/v), less than about 10% (v/v), less thanabout 5% (v/v), or less than about 1% (v/v). In other aspects of thisembodiment, a pharmaceutical composition disclosed herein may comprise asolvent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v),about 1% (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about 1% (v/v)to 50% (v/v), about 1% (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v),about 1% (v/v) to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v)to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v),about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v)to 50% (v/v), about 4% (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v),about 4% (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v)to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v),about 6% (v/v) to 20% (v/v), about 6% (v/v) to 10% (v/v), about 8% (v/v)to 50% (v/v), about 8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v),about 8% (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8%(v/v) to 12% (v/v).

In one embodiment, a solvent may comprise a pharmaceutically acceptablealcohol. As used herein, the term “alcohol” refers to an organicmolecule comprising a hydroxyl functional group (—OH) bonded to a carbonatom, where the carbon atom is saturated. In aspects of this embodiment,the alcohol may be, e.g., a C₁₋₄ alcohol, a C₂₋₄ alcohol, a C₁₋₅alcohol, a C₁₋₇ alcohol, a C₁₋₁₀ alcohol, a C₁₋₁₅ alcohol, or a C₁₋₂₀alcohol. In other aspects of this embodiment, an alcohol may be, e.g., aprimary alcohol, a secondary alcohol, or a tertiary alcohol. In otheraspects of this embodiment, an alcohol may be, e.g., an acyclic alcohol,a monohydric alcohol, a polyhydric alcohol (also known as a polyol orsugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol,or a combination thereof. Examples of a monohydric alcohol include,without limitation, methanol, ethanol, propanol, butanol, pentanol, and1-hexadecanol. Examples of a polyhydric alcohol include, withoutlimitation, glycol, glycerol, arabitol, erythritol, xylitol, maltitol,sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol),and isomalt. Examples of an unsaturated aliphatic alcohol include,without limitation, prop-2-ene-1-ol, 3,7-dimethylocta-2,6-dien-1-ol, andprop-2-in-1-ol. Examples of an alicyclic alcohol include, withoutlimitation, cyclohexane-1,2,3,4,5,6-hexyl and2-(2-propyl)-5-methyl-cyclohexane-1-ol.

In another embodiment, a solvent may comprise an ester ofpharmaceutically acceptable alcohol and an acid. Suitablepharmaceutically acceptable alcohols include the ones disclosed herein.Suitable acids include, without limitation, acetic acid, butaric acid,and formic acid. An ester of an alcohol and an acid include, withoutlimitation, methyl acetate, methyl buterate, methyl formate, ethylacetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate,propyl formate, butyl acetate, butyl buterate, butyl formate, isobutylacetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentylbuterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate,and 1-hexadecyl formate.

In another embodiment, a solvent may comprise a pharmaceuticallyacceptable polyethylene glycol (PEG) polymer. PEG polymers, also knownas polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers,are prepared by polymerization of ethylene oxide and are commerciallyavailable over a wide range of molecular weights from 100 g/mol to10,000,000 g/mol. PEG polymers with a low molecular mass are liquids orlow-melting solids, whereas PEG polymers of a higher molecular mass aresolids. A PEG polymer include, without limitation, PEG 100, PEG 200, PEG300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG8500, PEG 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, PEG19,000, or PEG 20,000.

In another embodiment, a solvent may comprise a pharmaceuticallyacceptable glyceride. Glycerides comprise a substituted glycerol, whereone, two, or all three hydroxyl groups of the glycerol are eachesterified using a fatty acid to produce monoglycerides, diglycerides,and triglycerides, respectively. In these compounds, each hydroxylgroups of glycerol may be esterified by different fatty acids.Additionally, glycerides may be acetylated to produce acetylatedmonoglycerides, acetylated diglycerides, and acetylated triglycerides.

In one embodiment, a solvent may comprise a pharmaceutically acceptablesolid solvent. Solid solvents may be useful in the manufacture of asolid dose formulation of a pharmaceutical composition disclosed herein.Typically, a solid solvent is melted in order to dissolve a therapeuticcompound. A pharmaceutically acceptable solid solvent includes, withoutlimitation, menthol and PEG polymers described above.

Aspects of the present specification disclose, in part, apharmaceutically acceptable adjuvant. An adjuvant is a pharmacologicalagent that modifies the effect of other agents, such as one or moretherapeutic compounds disclosed herein. In addition, an adjuvantdisclosed herein may be used as a solvent that dissolves a therapeuticcompound disclosed herein, forming an adjuvant solution. An adjuvant mayfacilitate delivery of a therapeutic compound in a manner that moreeffectively inhibits a pro-inflammatory response. In one embodiment, anadjuvant facilitates the delivery of a therapeutic compound intomacrophages.

A pharmaceutical composition may comprise a pharmaceutically acceptableadjuvant in an amount sufficient to mix with a solution or an emulsion.In other aspects of this embodiment, a pharmaceutical composition maycomprise an adjuvant in an amount of, e.g., at least 10% (v/v), at least20% (v/v), at least 30% (v/v), at least 35% (v/v), at least 40% (v/v),at least 45% (v/v), at least 50% (v/v), at least 55% (v/v), at least 60%(v/v), at least 65% (v/v), at least 70% (v/v), at least 75% (v/v), atleast 80% (v/v), at least 85% (v/v), at least 90% (v/v), at least 95%(v/v), or at least 99% (v/v). In other aspects of this embodiment, apharmaceutical composition may comprise an adjuvant in an amount in arange of, e.g., about 30% (v/v) to about 99% (v/v), about 35% (v/v) toabout 99% (v/v), about 40% (v/v) to about 99% (v/v), about 45% (v/v) toabout 99% (v/v), about 50% (v/v) to about 99% (v/v), about 30% (v/v) toabout 98% (v/v), about 35% (v/v) to about 98% (v/v), about 40% (v/v) toabout 98% (v/v), about 45% (v/v) to about 98% (v/v), about 50% (v/v) toabout 98% (v/v), about 30% (v/v) to about 95% (v/v), about 35% (v/v) toabout 95% (v/v), about 40% (v/v) to about 95% (v/v), about 45% (v/v) toabout 95% (v/v), or about 50% (v/v) to about 95% (v/v). In yet otheraspects of this embodiment, a pharmaceutical composition may comprise anadjuvant in an amount in a range of, e.g., about 70% (v/v) to about 97%(v/v), about 75% (v/v) to about 97% (v/v), about 80% (v/v) to about 97%(v/v), about 85% (v/v) to about 97% (v/v), about 88% (v/v) to about 97%(v/v), about 89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97%(v/v), about 75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96%(v/v), about 85% (v/v) to about 96% (v/v), about 88% (v/v) to about 96%(v/v), about 89% (v/v) to about 96% (v/v), about 90% (v/v) to about 96%(v/v), about 75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93%(v/v), about 85% (v/v) to about 93% (v/v), about 88% (v/v) to about 93%(v/v), about 89% (v/v) to about 93% (v/v), or about 90% (v/v) to about93% (v/v).

In one embodiment, an adjuvant may be a pharmaceutically acceptablelipid. A lipid may be broadly defined as a hydrophobic or amphiphilicsmall molecule. The amphiphilic nature of some lipids allows them toform structures such as vesicles, liposomes, or membranes in an aqueousenvironment. Non-limiting examples, of lipids include fatty acids,glycerolipids (like monoglycerides, diglycerides, and triglycerides),phospholipids, sphingolipids, sterol lipids, prenol lipids,saccharolipids, and polyketides. A pharmaceutical composition disclosedherein may comprise a lipid such as, e.g. an oil, an oil-based liquid, afat, a fatty acid, a wax, a fatty acid ester, a fatty acid salt, a fattyalcohol, a glyceride (mono-, di- or tri-glyceride), a phospholipids, aglycol ester, a sucrose ester, a glycerol oleate derivative, a mediumchain triglyceride, or a mixture thereof.

A lipid useful in the pharmaceutical compositions may be apharmaceutically acceptable fatty acid. A fatty acid comprises acarboxylic acid with a long unbranched hydrocarbon chain which may beeither saturated or unsaturated. Thus arrangement confers a fatty acidwith a polar, hydrophilic end, and a nonpolar, hydrophobic end that isinsoluble in water. Most naturally occurring fatty acids have ahydrocarbon chain of an even number of carbon atoms, typically between 4and 24 carbons, and may be attached to functional groups containingoxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fattyacids may have a hydrocarbon chain of any number of carbon atoms frombetween 3 and 40 carbons. Where a double bond exists, there is thepossibility of either a cis or a trans geometric isomerism, whichsignificantly affects the molecule's molecular configuration. Cis-doublebonds cause the fatty acid chain to bend, an effect that is morepronounced the more double bonds there are in a chain. Most naturallyoccurring fatty acids are of the cis configuration, although the transform does exist in some natural and partially hydrogenated fats andoils. Examples of fatty acids include, without limitation, capryllicacid (8:0), pelargonic acid (9:0), capric acid (10:0), undecylic acid(11:0), lauric acid (12:0), tridecylic acid (13:0), myristic acid(14:0), myristoleic acid (14:1), pentadecyclic acid (15:0), palmiticacid (16:0), palmitoleic acid (16:1), sapienic acid (16:1), margaricacid (17:0), stearic acid (18:0), oleic acid (18:1), elaidic acid(18:1), vaccenic acid (18:1), linoleic acid (18:2), linoelaidic acid(18:2), α-linolenic acid (18:3), γ-linolenic acid (18:3), stearidonicacid (18:4), nonadecylic acid (19:0), arachidic acid (20:0), eicosenoicacid (20:1), dihomo-γ-linolenic acid (20:3), mead acid (20:3),arachidonic acid (20:4), eicosapentaenoic acid (20:5), heneicosylic acid(21:0), behenic acid (22:0), erucic acid (22:1), docosahexaenoic acid(22:6), tricosylic acid (23:0), lignoceric acid (24:0), nervonic acid(24:1), pentacosylic acid (25:0), cerotic acid (26:0), heptacosylic acid(27:0), montanic acid (28:0), nonacosylic acid (29:0), melissic acid(30:0), henatriacontylic acid (31:0), lacceroic acid (32:0), psyllicacid (33:0), geddic acid (34:0), ceroplastic acid (35:0), andhexatriacontylic acid (36:0).

In an embodiment, an adjuvant may be a pharmaceutically acceptablesaturated or unsaturated fatty acid. A saturated or unsaturated fattyacid may comprise, e.g., at least 8, at least 10, at least 12, at least14, at least 16, at least 18, at least 20, at least 22, at least 24, atleast 26, at least 28, or at least 30 carbon atoms. In some instances, asaturated or unsaturated fatty acid comprises, e.g., between 4 and 24carbon atoms, between 6 and 24 carbon atoms, between 8 and 24 carbonatoms, between 10 and 24 carbon atoms, between 12 and 24 carbon atoms,between 14 and 24 carbon atoms, or between 16 and 24 carbon atoms,between 4 and 22 carbon atoms, between 6 and 22 carbon atoms, between 8and 22 carbon atoms, between 10 and 22 carbon atoms, between 12 and 22carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22carbon atoms, between 4 and 20 carbon atoms, between 6 and 20 carbonatoms, between 8 and 20 carbon atoms, between 10 and 20 carbon atoms,between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, orbetween 16 and 20 carbon atoms. If unsaturated, the fatty acid may have,e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 ormore double bonds.

A pharmaceutically acceptable saturated or unsaturated fatty acid may beliquid at room temperature. The melting point of a fatty acid is largelydetermined by the degree of saturation/unsaturation of the hydrocarbonchain. In aspects of this embodiment, a saturated or unsaturated fattyacid has a melting point temperature of, e.g., 20° C. or below, 15° C.or below, 10° C. or below, 5° C. or below, 0° C. or below, −5° C. orbelow, −10° C. or below, −15° C. or below, or −20° C. or below. In otheraspects of this embodiment, a saturated or unsaturated fatty acid has amelting point temperature in the range of, e.g., about −20° C. to about20° C., about −20° C. to about 18° C., about −20° C. to about 16° C.,about −20° C. to about 12° C., about −20° C. to about 8° C., about −20°C. to about 4° C., about −20° C. to about 0° C., about −15° C. to about20° C., about −15° C. to about 18° C., about −15° C. to about 16° C.,about −15° C. to about 12° C., about −15° C. to about 8° C., about −15°C. to about 4° C., or about −15° C. to about 0° C.

In another embodiment, an adjuvant may comprise one kind ofpharmaceutically acceptable fatty acid. An adjuvant may comprise, forexample, only palmitic acid, only stearic acid, only oleic acid, onlylinoleic acid, or only linolenic acid. Alternatively, an adjuvant maycomprise a plurality of different pharmaceutically acceptable fattyacids. An adjuvant may comprise, e.g., two or more different fattyacids, three or more different fatty acids, four or more different fattyacids, five or more different fatty acids, or six or more differentfatty acids.

In other aspects of this embodiment, an adjuvant may comprise two ormore different pharmaceutically acceptable fatty acids including atleast palmitic acid, stearic acid, oleic acid, linoleic acid and/orlinolenic acid, and any combination thereof. An adjuvant may comprise aratio of palmitic acid and/or stearic acid and/or oleic acid:linolenicacid and/or linoleic acid of, e.g., at least 2:1, at least 3:1, at least4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least9:1, at least 10:1, at least 15:1, or at least 20:1. In some examples,an adjuvant may comprise a ratio of palmitic acid and/or stearic acidand/or oleic acid:linolenic acid and/or linoleic acid in a range of,e.g., about 1:1 to about 20:1, about 2:1 to about 15:1, about 4:1 toabout 12:1, or about 6:1 to about 10:1.

In other aspects of this embodiment, an adjuvant may comprise four ormore different pharmaceutically acceptable fatty acids including atleast palmitic acid, stearic acid, oleic acid, linoleic acid and/orlinolenic acid, and any combination thereof. In other aspects of thisembodiment, an adjuvant may comprise a ratio of palmitic acid:stearicacid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, 8:8:1:1,7:7:1:1, 6:6:1:1, 5:5:1:1, 4:4:1:1, 3:3:1:1, 2:2:1:1, or 1:1:1:1. Inother aspects of this embodiment, an adjuvant may comprise a ratio ofpalmitic acid:stearic acid:linolenic acid:linoleic acid in a range of,e.g., about 10:10:1:1 to about 6:6:1:1, about 8:8:1:1 to about 4:4:1:1,or about 5:5:1:1 to about 1:1:1:1.

A lipid useful in the pharmaceutical compositions may be apharmaceutically acceptable omega fatty acid. Non-limiting examples ofan omega fatty acid include omega-3, omega-6, and omega-9. Omega-3 fattyacids (also known as n-3 fatty acids or ω-3 fatty acids) are a family ofessential unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-3 position, that is, the third bond,counting from the methyl end of the fatty acid. The omega-3 fatty acidsare “essential” fatty acids because they are vital for normal metabolismand cannot be synthesized by the human body. An omega-3 fatty acidincludes, without limitation, hexadecatrienoic acid (16:3), α-linolenicacid (18:3), stearidonic acid (18:4), eicosatrienoic acid (20:3),eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5),heneicosapentaenoic acid (21:5), docosapentaenoic acid (22:5),clupanodonic acid (22:5), docosahexaenoic acid (22:6),tetracosapentaenoic acid (24:5), and tetracosahexaenoic acid (nisinicacid) (24:6).

Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids)are a family of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-6 position, that is, the sixth bond,counting from the methyl end of the fatty acid. An omega-6 fatty acidincludes, without limitation, linoleic acid (18:2), gammα-linolenic acid(18:3), calendic acid (18:3), eicosadienoic acid (20:2),dihomo-gammα-linolenic acid (20:3), arachidonic acid (20:4),docosadienoic acid (22:2), adrenic acid (22:4), docosapentaenoic acid(22:5), tetracosatetraenoic acid (24:4), and tetracosapentaenoic acid(24:5). Omega-9 fatty acids (also known as n-9 fatty acids or ω-9 fattyacids) are a family of unsaturated fatty acids that have in common afinal carbon-carbon double bond in the n-9 position, that is, the ninthbond, counting from the methyl end of the fatty acid. An omega-9 fattyacid includes, without limitation, oleic acid (18:1), elaidic acid(18:1), eicosenoic acid (20:1), mead acid (20:3), erucic acid (22:1),and nervonic acid (24:1).

A lipid useful in the pharmaceutical compositions disclosed herein maybe a pharmaceutically acceptable oil. An oil includes any fatty acidthat is liquid at normal room temperature, such as, e.g. about 20° C. Incontrast, a fat includes any fatty acid that is solid at normal roomtemperature, such as, e.g. about 20° C. An oil suitable as a lipiduseful in the pharmaceutical compositions disclosed herein, may be anatural oil or a vegetable oil. Examples of suitable natural oilsinclude, without limitation, mineral oil, triacetin, ethyl oleate, ahydrogenated natural oil, or a mixture thereof. Examples of suitablevegetable oils include, without limitation, almond oil, arachis oil,avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseedoil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seedoil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil,safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnutoil, wheat germ oil, or a mixture thereof. Each of these oils iscommercially available from a number of sources well recognized by thoseskilled in the art.

An oil is typically a mixture of various fatty acids. For example,rapeseed oil, obtained from the seeds of brassica napus, includes bothomega-6 and omega-3 fatty acids in a ratio of about 2:1. As anotherexample, linseed oil, obtained from the seeds of linum usitatissimum,includes about 7% palmitic acid, about 3.4-4.6% stearic acid, about18.5-22.6% oleic acid, about 14.2-17% linoleic acid, and about51.9-55.2% α-linolenic acid. In some instances, a pharmaceuticalcomposition comprises an oil including at least two different fattyacids, at least three different fatty acids, at least four differentfatty acids, at least five different fatty acids, or at least sixdifferent fatty acids.

A lipid useful in the pharmaceutical compositions may be apharmaceutically acceptable glycerolipid. Glycerolipids are composedmainly of mono-, di-, and tri-substituted glycerols. One group ofglycerolipids is the glycerides, where one, two, or all three hydroxylgroups of glycerol are each esterified using a fatty acid to producemonoglycerides, diglycerides, and triglycerides, respectively. In thesecompounds, each hydroxyl groups of glycerol may be esterified bydifferent fatty acids. Additionally, glycerides may be acetylated toproduce acetylated monoglycerides, acetylated diglycerides, andacetylated triglycerides. One group of glycerolipids is the glycerides,where one, two, or all three hydroxyl groups of glycerol have sugarresidues attached via a glycosidic linkage.

In some instances, compositions may include one or more pharmaceuticallyacceptable stabilizing agents. A stabilizing agent reduces or eliminatesformation of esters of a therapeutic compound that may result as aunwanted reaction with the particular solvent used. A stabilizing agentinclude, without limitation, water, a sacrificial acid comprising afatty acid component and acetic acid, ethyl acetate, a sodiumacetate/acetic acid (E262), a monoglyceride, an acetylatedmonoglyceride, a diglyceride, an acetylated monoglyceride, an acetylateddiglyceride, a fatty acid, and a fatty acid salt.

In one embodiment, a pharmaceutically acceptable stabilizing agent maycomprise a pharmaceutically acceptable emulsifying agent. An emulsifyingagent (also known as an emulgent) is a substance that stabilizes anemulsion comprising a liquid dispersed phase and a liquid continuousphase by increasing its kinetic stability. Thus, in situations where thesolvent and adjuvant used to make a pharmaceutical composition disclosedherein are normally immiscible, an emulsifying agent disclosed herein isused to create a homogenous and stable emulsion. An emulsifying agentincludes, without limitation, a surfactant, a polysaccharide, a lectin,and a phospholipid.

In an aspect of this embodiment, an emulsifying agent may comprise asurfactant. As used hereon, the term “surfactant” refers to a natural orsynthetic amphiphilic compound. A surfactant can be non-ionic,zwitterionic, or ionic. Non-limiting examples of surfactants includepolysorbates like polysorbate 20 (TWEEN® 20), polysorbate 40 (TWEEN®40), polysorbate 60 (TWEEN® 60), polysorbate 61 (TWEEN® 61), polysorbate65 (TWEEN® 65), polysorbate 80 (TWEEN® 80), and polysorbate 81 (TWEEN®81); poloxamers (polyethylene-polypropylene copolymers), such asPoloxamer 124 (PLURONIC® L44), Poloxamer 181 (PLURONIC® L61), Poloxamer182 (PLURONIC® L62), Poloxamer 184 (PLURONIC® L64), Poloxamer 188(PLURONIC® F68), Poloxamer 237 (PLURONIC® F87), Poloxamer 338 (PLURONIC®L108), Poloxamer 407 (PLURONIC® F127), polyoxyethyleneglycol dodecylethers, such as BRIJ® 30, and BRIJ® 35; 2-dodecoxyethanol (LUBROL®-PX);polyoxyethylene octyl phenyl ether (TRITON® X-100); sodium dodecylsulfate (SDS); 3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate(CHAPS); 3-[(3 -cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO); sucrose monolaurate; and sodium cholate. Othernon-limiting examples of surfactant excipients can be found in, e.g.,Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, supra, (2001);and Rowe, supra, (2003), each of which is hereby incorporated byreference in its entirety.

In an aspect of this embodiment, an emulsifying agent may comprise apolysaccharide. Non-limiting examples of polysaccharides include guargum, agar, alginate, calgene, a dextran (like dextran 1K, dextran 4K,dextran 40K, dextran 60K, and dextran 70K), dextrin, glycogen, inulin,starch, a starch derivative (like hydroxymethyl starch, hydroxyethylstarch, hydroxypropyl starch, hydroxybutyl starch, and hydroxypentylstarch), hetastarch, cellulose, FICOLL, methyl cellulose (MC),carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (NEMC),hydroxypropyl methyl cellulose (HPMC); polyvinyl acetates (PVA);polyvinyl pyrrolidones (PVP), also known as povidones, having a K-valueof less than or equal to 18, a K-value greater than 18 or less than orequal to 95, or a K-value greater than 95, like PVP 12 (KOLLIDON® 12),PVP 17 (KOLLIDON® 17), PVP 25 (KOLLIDON® 25), PVP 30 (KOLLIDON® 30), PVP90 (KOLLIDON® 90); and polyethylene imines (PEI).

In an aspect of this embodiment, an emulsifying agent may comprise alectin. Lectins are sugar-binding proteins that are highly specific fortheir sugar moieties. Lectins may be classified according to the sugarmoiety that they bind to, and include, without limitation,mannose-binding lectins, galactose/N-acetylgalactosamine-bindinglectins, N-acetylgluxosamine-binding lectins, N-acetylneuramine-bindinglectins, N-acetylneuraminic acid-binding lectins, and fucose-bindinglectins. Non-limiting examples of surfactants include concanavain A,lentil lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairyvetch lectin, wheat germ agglutinin, elderberry lectin, Maackiaanurensis leukoagglutinin, Maackia anurensis hemoagglutinin, Ulexeuropaeus agglutinin, and Aleuria aurantia lectin.

In an aspect of this embodiment, an emulsifying agent may comprise aphospholipid. The structure of the phospholipid generally comprises ahydrophobic tail and a hydrophilic head and is amphipathic in nature.Most phospholipids contain a diglyceride, a phosphate group, and asimple organic molecule such as choline; one exception to this rule issphingomyelin, which is derived from sphingosine instead of glycerol.Phospholipids include, without limitation, diacylglycerides andphosphosphingolipids. Non-limiting examples of diacylglycerides includea phosphatidic acid (phosphatidate) (PA), a phosphatidylethanolamine(cephalin) (PE), a phosphatidylcholine (lecithin) (PC), aphosphatidylserine (PS), and a phosphoinositide includingphosphatidylinositol (PI), phosphatidylinositol phosphate (PIP),phosphatidylinositol bisphosphate (PIP2), and phosphatidylinositoltriphosphate (PIP3). Non-limiting examples of phosphosphingolipidsinclude a ceramide phosphorylcholine (sphingomyelin) (SPH), ceramidephosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramidephosphorylglycerol.

In one embodiment, a pharmaceutically acceptable stabilizing agent doesnot comprise a pharmaceutically acceptable emulsifying agent.

In another embodiment, a pharmaceutical composition does not comprise apharmaceutically acceptable emulsifying agent.

The pharmaceutical compositions may act as a delivery system thatenables the therapeutic compound(s) to be more effectively delivered ortargeted to a cell type, tissue, organ, or region of the body in amanner that more effectively inhibits a pro-inflammatory response. Thisinhibition results in an improved treatment of a chronic inflammation.For example, a pharmaceutical composition may facilitate the delivery ofa therapeutic compound disclosed herein into macrophages. One possiblemechanism that achieves this selective biodistribution is that thepharmaceutical compositions disclosed herein may be designed to takeadvantage of the activity of chylomicrons. Chylomicrons are relativelylarge lipoprotein particles having a diameter of 75 nm to 1,200 nm.Comprising triglycerides (85-92%), phospholipids (6-12%), cholesterol(1-3%) and apolipoproteins (1-2%), chylomicrons transport dietary lipidsfrom the intestines to other locations in the body. Chylomicrons are oneof the five major groups of lipoproteins, the others being VLDL, IDL,low-density lipoproteins (LDL), high-density lipoproteins (HDL), thatenable fats and cholesterol to move within the water-based solution ofthe bloodstream.

During digestion, fatty acids and cholesterol undergo processing in thegastrointestinal tract by the action of pancreatic juices includinglipases and emulsification with bile salts to generate micelles. Thesemicelles allow the absorption of lipid as free fatty acids by theabsorptive cells of the small intestine, known as enterocytes. Once inthe enterocytes, triglycerides and cholesterol are assembled intonascent chylomicrons. Nascent chylomicrons are primarily composed oftriglycerides (85%) and contain some cholesterol and cholesteryl esters.The main apolipoprotein component is apolipoprotein B-48 (APOB48). Thesenascent chylomicrons are released by exocytosis from enterocytes intolacteals, lymphatic vessels originating in the villi of the smallintestine, and are then secreted into the bloodstream at the thoracicduct's connection with the left subclavian vein.

While circulating in lymph and blood, chylomicrons exchange componentswith HDL. The HDL donates apolipoprotein C-II (APOC2) and apolipoproteinE (APOE) to the nascent chylomicron and thus converts it to a maturechylomicron (often referred to simply as “chylomicron”). APOC2 is thecofactor for lipoprotein lipase (LPL) activity. Once triglyceride storesare distributed, the chylomicron returns APOC2 to the HDL (but keepsAPOE), and, thus, becomes a chylomicron remnant, now only 30-50 nm.APOB48 and APOE are important to identify the chylomicron remnant in theliver for endocytosis and breakdown into lipoproteins (VLDL, LDL andHDL). These lipoproteins are processed and stored by competent cells,including, e.g., hepatocytes, adipocytes and macrophages. Thus, withoutwishing to be limited by any theory, upon oral administration of thepharmaceutical compositions disclosed herein are processed into micelleswhile in the gastrointestinal tract, absorbed by enterocytes andassembled into nascent chylomicrons, remain associated with chylomicronremnants taken up by the liver, and ultimately loaded into macrophages.

Aspects of the present specification disclose, in part, a method ofpreparing a pharmaceutical composition disclosed herein. A methoddisclosed herein comprises the step of contacting a pharmaceuticallyacceptable adjuvant disclosed herein with a therapeutic compounddisclosed herein under conditions which allow the therapeutic compoundto dissolve in the pharmaceutically acceptable adjuvant, thereby forminga pharmaceutical composition disclosed herein.

Other aspects of the present specification include a method of preparinga pharmaceutical composition. A method may comprise the steps of a)contacting a pharmaceutically acceptable solvent with a therapeuticcompound under conditions which allow the therapeutic compound todissolve in the pharmaceutically acceptable solvent, thereby forming asolution; and b) contacting the solution formed in step (a) with apharmaceutically acceptable adjuvant disclosed herein under conditionswhich allow the formation of a pharmaceutical composition. The methodsof preparing may further comprise a step (c) of removing thepharmaceutically acceptable solvent from the pharmaceutical composition.

The amount of therapeutic compound that is contacted with thepharmaceutically acceptable solvent in step (a) of the method may varywidely. Factors that may influence the amount of a therapeutic compoundused include, among others, the final amount the therapeutic compounddesired in the pharmaceutical composition, the desired concentration ofa therapeutic compound in the solution, the hydrophobicity of thetherapeutic compound, the lipophobicity of the therapeutic compound, thetemperature under which the contacting step (a) is performed, and thetime under which the contacting step (a) is performed.

The volume of a pharmaceutically acceptable solvent used in step (a) ofthe method also may vary over a wide range. Factors that may influencethe volume of pharmaceutically acceptable solvent used include, amongothers, the final amount of pharmaceutical composition desired, thedesired concentration of a therapeutic compound in the solution, thehydrophobicity of the therapeutic compound, and the lipophobicity of thetherapeutic compound.

In aspects of this embodiment, the amount of a therapeutic compound thatis contacted with the solvent in step (a) may be, e.g., at least 10 mg,at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg,at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, atleast 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, atleast 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg,at least 1,400 mg, or at least 1,500 mg. In other aspects of thisembodiment, the amount of a therapeutic compound that is contacted withthe solvent in step (a) may be in the range of, e.g., about 10 mg toabout 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg,about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mgto about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, orabout 1,000 mg to about 1,500 mg. In other aspects of this embodiment,the amount of a therapeutic compound that is dissolved in the solvent instep (a) may be in the range of, e.g., about 10 mg to about 250 mg,about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg toabout 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg toabout 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg,about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mgto about 1,000 mg, or about 200 mg to about 1,500 mg.

Step (a) may be carried out at room temperature, in order to allow atherapeutic compound to dissolve fully in the pharmaceuticallyacceptable solvent. However, in other embodiments of the method, step(a) may be carried out at a temperature that is greater than roomtemperature, e.g., greater than 21° C., greater than 25° C., greaterthan 30° C., greater than 35° C. or greater than 3TC. In certain cases,Step (a) may be carried out at temperatures below room temperature, inorder to allow a therapeutic compound to dissolve fully in solvent.However, in other embodiments of the method, step (a) may be carried outat a temperature that is less than room temperature, e.g., less than 10°C., greater than 5° C., greater than 0° C., greater than −10° C. orgreater than −20° C. The contacting in Step (a) may comprise mixing thetherapeutic compound and the pharmaceutically acceptable solvent, e.g.,by stirring, inversion, sonication, or vortexing. The mixing may becarried out for, e.g., at least 1 second, at least 5 seconds, at least10 seconds, at least 20 seconds, at least 30 seconds, at least 45seconds, at least 60 seconds, or more, until the therapeutic compound isfully dissolved in the solvent.

The concentration of a therapeutic compound in a solution may vary overa wide range. By way of example, the concentration of the therapeuticcompound may be at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL,at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, atleast 1,000 mg/mL, or at least 1,200 mg/mL. The concentration of thetherapeutic compound may be, e.g., at most 1,000 mg/mL, at most 1,100mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, atmost 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most3,000 mg/mL. In some instances, the concentration of a therapeuticcompound may be in a range of, e.g., about 0.00001 mg/mL to about 3,000mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL toabout 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mLto about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL,about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 250 mg/mL toabout 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750 mg/mLto about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about 100mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, about500 mg/mL to about 1,200 mg/mL, about 750 mg/mL to about 1,200 mg/mL,about 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to about 1,000mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about1,000 mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL toabout 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500 mg/mL toabout 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250 mg/mL toabout 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL toabout 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mLto about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

The volume of a pharmaceutically acceptable adjuvant used in step (b) ofthe method may be any volume desired. Factors used to determine thevolume of a pharmaceutically acceptable adjuvant used include, withoutlimitation, the final amount of a pharmaceutical composition desired,the desired concentration of a therapeutic compound in thepharmaceutical composition, the ratio of solvent:adjuvant used, and themiscibility of solvent and adjuvant.

In aspects of this embodiment, the ratio of solution:adjuvant may be,e.g., at least 5:1, at least 4:1, at least 3:1, at least 2:1, at least0:1, at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least1:10, at least 1:15, at least 1:20, or at least 1:25. In other aspectsof this embodiment, the ratio of solution:adjuvant may be in a range of,e.g., about 5:1 to about 1:25, about 4:1 to about 1:25, about 3:1 toabout 1:25, about 2:1 to about 1:25, about 0:1 to about 1:25, about 1:1to about 1:25, about 1:2 to about 1:25, about 1:3 to about 1:25, about1:4 to about 1:25, about 1:5 to about 1:25, about 5:1 to about 1:20,about 4:1 to about 1:20, about 3:1 to about 1:20, about 2:1 to about1:20, about 0:1 to about 1:20, about 1:1 to about 1:20, about 1:2 toabout 1:20, about 1:3 to about 1:20, about 1:4 to about 1:20, about 1:5to about 1:20, about 5:1 to about 1:15, about 4:1 to about 1:15, about3:1 to about 1:15, about 0:1 to about 1:15, about 2:1 to about 1:15,about 1:1 to about 1:15, about 1:2 to about 1:15, about 1:3 to about1:15, about 1:4 to about 1:15, about 1:5 to about 1:15, about 5:1 toabout 1:12, about 4:1 to about 1:12, about 3:1 to about 1:12, about 2:1to about 1:12, about 0:1 to about 1:12, about 1:1 to about 1:12, about1:2 to about 1:12, about 1:3 to about 1:12, about 1:4 to about 1:12,about 1:5 to about 1:12, about 1:6 to about 1:12, about 1:7 to about1:12, about 1:8 to about 1:12, about 5:1 to about 1:10, about 4:1 toabout 1:10, about 3:1 to about 1:10, about 2:1 to about 1:10, about 0:1to about 1:10, about 1:1 to about 1:10, about 1:2 to about 1:10, about1:3 to about 1:10, about 1:4 to about 1:10, about 1:5 to about 1:10,about 1:6 to about 1:10, about 1:7 to about 1:10, or about 1:8 to about1:10.

Step (b) may be carried out at room temperature, in order to allow thesolution comprising the therapeutic compound to form the pharmaceuticalcomposition. However, in other embodiments of the method, step (b) maybe carried out at a temperature that is greater than room temperature,e.g., greater than 21° C., greater than 25° C., greater than 30° C.,greater than 35° C. or greater than 37° C. In certain cases, step (b)may be carried out at temperatures below room temperature, in order toallow a therapeutic compound to dissolve fully in a pharmaceuticallyacceptable solvent. However, in other embodiments of the method, step(b) may be carried out at a temperature that is less than roomtemperature, e.g., less than 10° C., greater than 5° C., greater than 0°C., greater than −10° C. or greater than −20° C. The contacting in step(b) may comprise mixing the solution and the pharmaceutically acceptableadjuvant, e.g., by stirring, inversion, sonication, or vortexing. Themixing may be carried out for, e.g., at least 1 second, at least 5seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds,at least 45 seconds, at least 60 seconds, or more, until thepharmaceutical composition is formed.

In step (c), the solvent removal from a pharmaceutical composition maybe accomplished using one of a variety of procedures known in the art,including, without limitation, evaporation, dialyzation, distillation,lypholization, and filtration. These removal procedures may be doneunder conditions of ambient atmosphere, under low pressure, or under avacuum.

In one embodiment, step (c) may result in the complete removal of apharmaceutically acceptable solvent from the pharmaceutical compositiondisclosed herein. In aspects of this embodiment, step (c) may result in,e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 93%, at least95%, at least 97%, or at least 99% removal of a pharmaceuticallyacceptable solvent from the pharmaceutical composition disclosed herein.

Step (c) is conducted at a temperature that allows for the evaporationof a pharmaceutically acceptable solvent disclosed herein, and as such,an evaporation temperature is solvent-dependent. Factors which influencean evaporation temperature of a solvent disclosed herein include,without limitation, the particular solvent used, the amount of solventpresent, the particular therapeutic compound present, the particularadjuvant present, the stability of the therapeutic compound present, thereactivity of the therapeutic compound present, the particularatmospheric pressure used, the time desired for complete evaporation.Generally, a pharmaceutical composition will require heating if theevaporation step is conducted at ambient pressure, e.g., 1 atm. However,under high vacuum conditions, the evaporation step may be conducted attemperatures below ambient temperature, e.g., less than 22° C.

In one embodiment, removal of solvent from the pharmaceuticalcomposition disclosed herein may be carried out at ambient atmosphericpressure and at a temperature above ambient temperature. In aspects ofthis embodiment, removal of solvent from the pharmaceutical compositionmay be carried out at ambient atmospheric pressure and at a temperatureof, e.g., more than 25° C., more than 30° C., more than 35° C., morethan 40° C., more than 45° C., more than 50° C., more than 55° C., morethan 60° C., more than 65° C., more than 70° C., more than 80° C., ormore than 85° C. In other aspects of this embodiment, removal of solventfrom the pharmaceutical composition may be carried out at ambientatmospheric pressure and at a temperature in a range of, e.g., about 25°C. to about 100° C., about 25° C. to about 95° C., about 25° C. to about90° C., about 25° C. to about 85° C., about 25° C. to about 80° C.,about 25° C. to about 75° C., about 25° C. to about 70° C., about 25° C.to about 65° C., or about 25° C. to about 60° C.

In another embodiment, removal of solvent from the pharmaceuticalcomposition may be carried out under vacuum and at a temperature belowambient temperature. In aspects of this embodiment, removal of solventfrom the pharmaceutical composition may be carried out under vacuum andat a temperature of, e.g., less than 20° C., less than 18° C., less than16° C., less than 14° C., less than 12° C., less than 10° C., less than8° C., less than 6° C., less than 4° C., less than 2° C., or less than0° C. In other aspects of this embodiment, removal of solvent from thepharmaceutical composition may be carried out under vacuum and at atemperature in a range of, e.g., about −20° C. to about 20° C., about−20° C. to about 18° C., about −20° C. to about 16° C., about −20° C. toabout 14° C., about −20° C. to about 12° C., about −20° C. to about 10°C., about −20° C. to about 8° C., about −20° C. to about 6° C., about−20° C. to about 4° C., about −20° C. to about 2° C., about −20° C. toabout 0° C., about −15° C. to about 20° C., about −10° C. to about 20°C., about -5° C. to about 20° C., about 0° C. to about 20° C., about−10° C. to about 20° C., about −10° C. to about 18° C., about −10° C. toabout 16° C., about −10° C. to about 14° C., about −10° C. to about 12°C., about −10° C. to about 10° C., about −10° C. to about 8° C., about−10° C. to about 6° C., about −10° C. to about 4° C., about −10° C. toabout 2° C., or about −10° C. to about 0° C.

The final concentration of a therapeutic compound in a pharmaceuticalcomposition disclosed herein may vary over a wide range and generallymay be characterized as a therapeutically effective amount. In someaspects, the final concentration of a therapeutic compound in apharmaceutical composition may be, e.g., at least 0.00001 mg/mL, atleast 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, atleast 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500mg/mL, at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200mg/mL. In other aspects of this embodiment, the concentration of atherapeutic compound disclosed herein in the solution may be, e.g., atmost 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects ofthis embodiment, the final concentration of a therapeutic compound in apharmaceutical composition may be in a range of, e.g., about 0.00001mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL,about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL toabout 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL,about 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about1,500 mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL toabout 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mLto about 1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL,about 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to about1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL toabout 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL toabout 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mLto about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL toabout 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mLto about 100 mg/mL.

A pharmaceutical composition produced using the methods disclosed hereinmay be a liquid formulation or a solid or semi-solid formulation. Aliquid formulation can be formed by using various lipids like oils ofother fatty acids that remain as liquids in the temperature rangedesired. In an embodiment, a pharmaceutical composition disclosed hereinis liquid at room temperature. In aspects of this embodiment, apharmaceutical composition disclosed herein may be formulated to be aliquid at a temperature of, e.g., about 25° C. or higher, about 23° C.or higher, about 21° C. or higher, about 19° C. or higher, about 17° C.or higher, about 15° C. or higher, about 12° C. or higher, about 10° C.or higher, about 8° C. or higher, about 6° C. or higher, about 4° C. orhigher, or about 0° C. or higher.

A solid or semi-solid formulation may take advantage of the differentmelting point temperatures of the various adjuvants like fatty acids.Formation of a solid or semi-solid dosage form can be by modifying therespective concentrations of the fatty acids comprising a pharmaceuticalcomposition disclosed herein. For example, linolenic acid has a meltingpoint temperature (T_(m)) of about −11cC , linoleic acid has a T_(m) ofabout −5° C., oleic acid has a T_(m) of about 16° C., palmitic acid hasa T_(m) of about 61-62° C., and Stearic acid has a T_(m) of about 67-72°C. Increasing the proportion(s) of palmitic, stearic or oleic acid wouldincrease the overall melting temperature of a composition, while,conversely, increasing the proportion(s) of linoleic and linolenic acidwould decrease the melting temperature of a composition. Thus, bycontrolling the types and amounts of the adjuvant components added, apharmaceutical composition disclosed herein can be made that issubstantially solid or semi-solid at room temperature, but melts when itis ingested, and reaches body temperature. The resulting meltedcomposition readily forms micelles which are absorbed by the intestine,assembled into chylomicrons, and ultimately absorbed by macrophages. Thesolid dosage form may be a powder, granule, tablet, capsule orsuppository.

Aspects of the present specification disclose a method of treating anindividual with a chronic inflammation. In one embodiment, the methodcomprises the step of administering to an individual in need thereof apharmaceutical composition as described herein, wherein administrationreduces a symptom associated with the chronic inflammation, therebytreating the individual.

Aspects of the present specification disclose, in part, treating anindividual suffering from a chronic inflammation. As used herein, theterm “treating,” refers to reducing or eliminating in an individual aclinical symptom of a chronic inflammation; or delaying or preventing inan individual the onset of a clinical symptom of a chronic inflammation.For example, the term “treating” can mean reducing a symptom of acondition characterized by a chronic inflammation by, e.g., at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% at least95%, or at least 100%. The actual symptoms associated with chronicinflammation are well known and can be determined by a person ofordinary skill in the art by taking into account factors, including,without limitation, the location of the chronic inflammation, the causeof the chronic inflammation, the severity of the chronic inflammation,and/or the tissue or organ affected by the chronic inflammation. Thoseof skill in the art will know the appropriate symptoms or indicatorsassociated with a specific type of chronic inflammation and will knowhow to determine if an individual is a candidate for treatment asdisclosed herein.

Chronic inflammation symptoms include, without limitation, edema,hyperemia, erythema, bruising, tenderness, stiffness, aches,swollenness, fever, chills, stuffy nose, stuffy head, breathingproblems, fluid retention, blood clots, loss of appetite, increasedheart rate, formation of granulomas, fibrinous, pus, non-viscous serousfluid, or ulcer and pain. The actual symptoms associated with a chronicinflammation are well known and can be determined by a person ofordinary skill in the art by taking into account factors, including,without limitation, the location of the inflammation, the cause of theinflammation, the severity of the inflammation, the tissue or organaffected, and the associated disorder.

Specific patterns of chronic inflammation are seen during particularsituations that arise in the body, such as when inflammation occurs onan epithelial surface, or pyogenic bacteria are involved. For example,granulomatous inflammation is an inflammation resulting from theformation of granulomas arising from a limited but diverse number ofdiseases, include, without limitation, tuberculosis, leprosy,sarcoidosis, and syphilis. Purulent inflammation is an inflammationresulting in large amount of pus, which consists of neutrophils, deadcells, and fluid. Infection by pyogenic bacteria such as staphylococciis characteristic of this kind of inflammation. Serous inflammation isan inflammation resulting from copious effusion of non-viscous serousfluid, commonly produced by mesothelial cells of serous membranes, butmay be derived from blood plasma. Skin blisters exemplify this patternof inflammation. Ulcerative inflammation is an inflammation resultingfrom the necrotic loss of tissue from the epithelial surface, exposinglower layers and forming an ulcer.

A chronic inflammation symptom can be associated with a large, unrelatedgroup of disorders which underlay a variety of diseases and disorders.The immune system is often involved with chronic inflammatory disorders,demonstrated in both allergic reactions and some myopathies, with manyimmune system disorders resulting in abnormal inflammation. Non-immunediseases with etiological origins in chronic inflammatory processesinclude cancer, atherosclerosis, and ischaemic heart disease.Non-limiting examples of disorders exhibiting chronic inflammation as asymptom include, without limitation, acne, acid reflux/heartburn, agerelated macular degeneration (AMD), allergy, allergic rhinitis,Alzheimer's disease, amyotrophic lateral sclerosis, anemia,appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmunedisorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullouspemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiacdisease, cellulitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, chronic obstructive pulmonary disease (COPD),cirrhosis, colitis, congestive heart failure, conjunctivitis, Crone'sdisease, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis,common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis,diabetes, diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, diabetic ulcer, digestive system disease, eczema,emphysema, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia,fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis,glomerulonephritis, glossitis, heart disease, heart valve dysfunction,hepatitis, hidradenitis suppurativa, Huntington's disease,hyperlipidemic pancreatitis, hypertension, ileitis, infection,inflammatory bowel disease, inflammatory cardiomegaly, inflammatoryneuropathy, insulin resistance, interstitial cystitis, interstitialnephritis, iritis, ischemia, ischemic heart disease, keratitis,keratoconjunctivitis, laryngitis, lupus nephritis, mastitis,mastoiditis, meningitis, metabolic syndrome (syndrome X), a migraine,multiple sclerosis, myelitis, myocarditis, myositis, nephritis,non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis,orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis,osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvicinflammatory disease, pemphigus vularis, pericarditis, peritonitis,pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis,proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis,pylephlebitis, renal failure, reperfusion injury, retinitis, rheumaticfever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis,spastic colon, stenosis, stomatitis, stroke, surgical complication,synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis,tonsillitis, trauma, traumatic brain injury, transplant rejection,trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis,vaginitis, vasculitis, and vulvitis.

In one embodiment, a chronic inflammation comprises a tissueinflammation. Tissue inflammation is a chronic inflammation that isconfined to a particular tissue or organ. In aspect of this embodiment,a tissue inflammation comprises, e.g., a skin inflammation, a muscleinflammation, a tendon inflammation, a ligament inflammation, a boneinflammation, a cartilage inflammation, a lung inflammation, a heartinflammation, a liver inflammation, a pancreatic inflammation, a kidneyinflammation, a bladder inflammation, a stomach inflammation, anintestinal inflammation, a neuron inflammation, and a braininflammation.

In another embodiment, a chronic inflammation comprises a systemicinflammation. Although the processes involved are identical to tissueinflammation, systemic inflammation is not confined to a particulartissue but in fact overwhelms the body, involving the endothelium andother organ systems. When it is due to infection, the term sepsis isapplied, with the terms bacteremia being applied specifically forbacterial sepsis and viremia specifically to viral sepsis. Vasodilationand organ dysfunction are serious problems associated with widespreadinfection that may lead to septic shock and death.

In another embodiment, a chronic inflammation comprises an arthritis.Arthritis includes a group of conditions involving damage to the jointsof the body due to the inflammation of the synovium including, withoutlimitation osteoarthritis, rheumatoid arthritis, juvenile idiopathicarthritis, spondyloarthropathies like ankylosing spondylitis, reactivearthritis (Reiter's syndrome), psoriatic arthritis, enteropathicarthritis associated with inflammatory bowel disease, Whipple diseaseand Behcet disease, septic arthritis, gout (also known as goutyarthritis, crystal synovitis, metabolic arthritis), pseudogout (calciumpyrophosphate deposition disease), and Still's disease. Arthritis canaffect a single joint (monoarthritis), two to four joints(oligoarthritis) or five or more joints (polyarthritis) and can beeither an auto-immune disease or a non-autoimmune disease.

In another embodiment, a chronic inflammation comprises an autoimmunedisorder. Autoimmune diseases can be broadly divided into systemic andorgan-specific autoimmune disorders, depending on the principalclinico-pathologic features of each disease. Systemic autoimmunediseases include, without limitation, systemic lupus erythematosus(SLE), Sjogren's syndrome, Scleroderma, rheumatoid arthritis andpolymyositis. Local autoimmune diseases may be endocrinologic (DiabetesMellitus Type 1, Hashimoto's thyroiditis, Addison's disease etc.),dermatologic (pemphigus vulgaris), hematologic (autoimmune haemolyticanemia), neural (multiple sclerosis) or can involve virtually anycircumscribed mass of body tissue. Types of autoimmune disordersinclude, without limitation, acute disseminated encephalomyelitis(ADEM), Addison's disease, an allergy or sensitivity, amyotrophiclateral sclerosis, anti-phospholipid antibody syndrome (APS), arthritis,autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner eardisease, autoimmune pancreatitis, bullous pemphigoid, celiac disease,Chagas disease, chronic obstructive pulmonary disease (COPD), diabetesmellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture'ssyndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto'sthyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenicpurpura, inflammatory bowel disease, interstitial cystitis, lupus(including discoid lupus erythematosus, drug-induced lupuserythematosus, lupus nephritis, neonatal lupus, subacute cutaneous lupuserythematosus and systemic lupus erythematosus), morphea, multiplesclerosis (MS), myasthenia gravis, myopathies, narcolepsy,neuromyotonia, pemphigus vulgaris, pernicious anaemia, primary biliarycirrhosis, recurrent disseminated encephalomyelitis (multiphasicdisseminated encephalomyelitis), rheumatic fever, schizophrenia,scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis, andvitiligo.

In another embodiment, a chronic inflammation comprises a myopathy.Myopathies are caused when the immune system inappropriately attackscomponents of the muscle, leading to inflammation in the muscle. Amyopathy includes an inflammatory myopathy and an auto-immune myopathy.Myopathies include, without limitation, dermatomyositis, inclusion bodymyositis, and polymyositis.

In another embodiment, a chronic inflammation comprises a vasculitis.Vasculitis is a varied group of disorders featuring inflammation of avessel wall including lymphatic vessels and blood vessels like veins(phlebitis), arteries (arteritis) and capillaries due to leukocytemigration and resultant damage. The inflammation may affect any sizeblood vessel, anywhere in the body. It may affect either arteries and/orveins. The inflammation may be focal, meaning that it affects a singlelocation within a vessel; or it may be widespread, with areas ofinflammation scattered throughout a particular organ or tissue, or evenaffecting more than one organ system in the body. Vasculitis include,without limitation, Buerger's disease (thromboangiitis obliterans),cerebral vasculitis (central nervous system vasculitis), Churg-Straussarteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis,giant cell (temporal) arteritis, Golfer's vasculitis, Henoch-Schonleinpurpura, hypersensitivity vasculitis (allergic vasculitis), Kawasakidisease, microscopic polyarteritis/polyangiitis, polyarteritis nodosa,polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu arteritis,Wegener's granulomatosis, and vasculitis secondary to connective tissuedisorders like systemic lupus erythematosus (SLE), rheumatoid arthritis(RA), relapsing polychondritis, Behcet's disease, or other connectivetissue disorders, vasculitis secondary to viral infection.

In another embodiment, a chronic inflammation comprises a skin disorder.Skin disorders include, without limitation, an acne, including acnevulgaris, a bullous phemigoid, a dermatitis, including atopic dermatitisand chronic actinic dermatitis, an eczema like atopic eczema, contacteczema, xerotic eczema, seborrhoeic dermatitis, dyshidrosis, discoideczema, venous eczema, dermatitis herpetiformis, neurodermatitis, andautoeczematization, and statis dermatitis, hidradenitis suppurativa,lichen planus, psoriasis including plaqure psoriasis, nail psoriasis,guttate psoriasis, scalp psoriasis, inverse psoriasis, pustularpsoriasis, erythrodermis psoriasis, and psoriatic arthritis, rosacea andscleroderma including morphea.

In another embodiment, a chronic inflammation comprises agastrointestinal disorder. A gastrointestinal disorder includes, withoutlimitation, irritable bowel disease, an inflammatory bowel diseaseincluding Crohn's disease and an ulcerative colitis like ulcerativeproctitis, left-sided colitis, pancolitis and fulminant colitis.

In another embodiment, a chronic inflammation comprises a cardiovasculardisease. When LDL cholesterol becomes embedded in arterial walls, it caninvoke an immune response. Chronic inflammation eventually can damagethe arteries, which can cause them to burst. Cardiovascular disease isany of a number of specific diseases that affect the heart itself and/orthe blood vessel system, especially the veins and arteries leading toand from the heart. There are more than 60 types of cardiovasculardisorders including, without limitation, a hypertension, endocarditis,myocarditis, heart valve dysfunction, congestive heart failure,myocardial infarction, a diabetic cardiac conditions, blood vesselinflammation like arteritis, phlebitis, vasculitis; arterial occlusivedisease like arteriosclerosis and stenosis, inflammatory cardiomegaly, aperipheral arterial disease; an aneurysm; an embolism; a dissection; apseudoaneurysm; a vascular malformation; a vascular nevus; a thrombosis;a thrombphlebitis; a varicose veins; a stroke. Symptoms of acardiovascular disorder affecting the heart include, without limitation,chest pain or chest discomfort (angina), pain in one or both arms, theleft shoulder, neck, jaw, or back, shortness of breath, dizziness,faster heartbeats, nausea, abnormal heartbeats, feeling fatigued.Symptoms of a cardiovascular disorder affecting the brain include,without limitation, sudden numbness or weakness of the face, arm, orleg, especially on one side of the body, sudden confusion or troublespeaking or understanding speech, sudden trouble seeing in one or botheyes, sudden dizziness, difficulty walking, or loss of balance orcoordination, sudden severe headache with no known cause. Symptoms of acardiovascular disorder affecting the legs, pelvis and/or arm include,without limitation, claudication, which is a pain, ache, or cramp in themuscles, and cold or numb feeling in the feet or toes, especially atnight.

In some aspects, a chronic inflammation comprises a cancer. Inflammationorchestrates the microenvironment around tumors, contributing toproliferation, survival and migration. For example, fibrinousinflammation results from a large increase in vascular permeabilitywhich allows fibrin to pass through the blood vessels. If an appropriateprocoagulative stimulus is present, such as cancer cells, a fibrinousexudate is deposited. This is commonly seen in serous cavities, wherethe conversion of fibrinous exudate into a scar can occur between serousmembranes, limiting their function. In another example, a cancer is aninflammatory cancer like a NF-κB-driven inflammatory cancer.

In some instances, drugs which otherwise may be effective for treatingcancers become ineffective or less effective due to the environment(“microenvironment”) created around tumors. These microenvironmentsnormally are associated with high levels of Reactive Oxygen Species(ROS), notably hydrogen peroxide. Fibroblasts also produce hydrogenperoxide. Oxidation also is prone to occur outside of cancer cells.

In one aspect, a therapeutic compound modifies a tumor microenvironment,such as by reducing the concentration of hydrogen peroxide and/or otherROS. By modifying the microenvironment in which a cancer thrives, thetherapeutic compound may help restore normal function of endogenousspecies. Further, modification of the microenvironment may improve theefficacy other cancer therapies, including chemo-therapies. To theextent that the presence of hydrogen peroxide and/or other ROS may beresponsible for oncogenesis, the therapeutic compound further mayfunction to prevent or delay the onset of a tumor. See, e.g., Poehlmannet al., “Repeated H₂O₂ exposure drives cell cycle progression in an invitro model of ulcerative colitis,” J Cell Mol. Med. 2013 Dec; 17(12):1619-1631.

In another embodiment, a chronic inflammation comprises apharmacologically-induced inflammation. Certain drugs or exogenicchemical compounds are known to affect inflammation. For example,Vitamin A deficiency causes an increase in an inflammatory response.Certain illicit drugs such as cocaine and ecstasy may exert some oftheir detrimental effects by activating transcription factors intimatelyinvolved with inflammation (e.g., NF-κB).

In another embodiment, a chronic inflammation comprises an infection. Aninfectious organism can escape the confines of the immediate tissue viathe circulatory system or lymphatic system, where it may spread to otherparts of the body. If an organism is not contained by the actions ofacute inflammation it may gain access to the lymphatic system via nearbylymph vessels. An infection of the lymph vessels is known aslymphangitis, and infection of a lymph node is known as lymphadenitis. Apathogen can gain access to the bloodstream through lymphatic drainageinto the circulatory system. Infections include, without limitation,bacterial cystitis, bacterial encephalitis, pandemic influenza, viralencephalitis, and viral hepatitis (A, B and C).

In another embodiment, a chronic inflammation comprises a tissue ororgan injury. Tissue or organ injuries include, without limitation, abum, a laceration, a wound, a puncture, or a trauma.

In another embodiment, a chronic inflammation comprises a transplantrejection. Transplant rejection occurs when a transplanted organ ortissue is not accepted by the body of the transplant recipient becausethe immune system of the recipient attacks the transplanted organ ortissue. An adaptive immune response, transplant rejection is mediatedthrough both T cell mediated and humoral immune (antibodies) mechanisms.A transplant rejection can be classified as a hyperacute rejection, anacute rejection, or a chronic rejection. Chronic rejection of atransplanted organ or tissue is where the rejection is due to a poorlyunderstood chronic inflammatory and immune response against thetransplanted tissue. Also included in the term “transplant rejection” isa graft-versus-host disease (GVHD). GVHD is a common complication ofallogeneic bone marrow transplantation in which functional immune cellsin the transplanted marrow recognize the recipient as “foreign” andmount an immunologic attack. It can also take place in a bloodtransfusion under certain circumstances. GVHD is divided into acute andchronic forms. Acute and chronic GVHD appear to involve different immunecell subsets, different cytokine profiles, somewhat different hosttargets, and respond differently to treatment.

In another embodiment, a chronic inflammation comprises a Th1-mediatedinflammatory disease. In a well-functioning immune system, an immuneresponse should result in a well-balanced pro-inflammatory Th1 responseand anti-inflammatory Th2 response that is suited to address the immunechallenge. Generally speaking, once a pro-inflammatory Th1 response isinitiated, the body relies on the anti-inflammatory response invoked bya Th2 response to counteract this Th1 response. This counteractiveresponse includes the release of Th2 type cytokines such as, e.g., IL-4,IL-5, and IL-13 which are associated with the promotion of IgE andeosinophilic responses in atopy, and also IL-10, which has ananti-inflammatory response. A Th1-mediated inflammatory disease involvesan excessive pro-inflammatory response produced by Th1 cells that leadsto chronic inflammation. The Th1-mediated disease may be virally,bacterially or chemically (e.g., environmentally) induced. For example,a virus causing the Th1-mediated disease may cause a chronic or acuteinfection, which may cause a respiratory disorder or influenza.

In another embodiment, a chronic inflammation comprises a chronicneurogenic inflammation. Chronic neurogenic inflammation refers to aninflammatory response initiated and/or maintained through the release ofinflammatory molecules like SP or CGRP which released from peripheralsensory nerve terminals (i.e., an efferent function, in contrast to thenormal afferent signaling to the spinal cord in these nerves). Chronicneurogenic inflammation includes both primary inflammation and secondaryneurogenic inflammation. As used herein, the term “primary neurogenicinflammation” refers to tissue inflammation (inflammatory symptoms) thatis initiated by, or results from, the release of substances from primarysensory nerve terminals (such as C and A-delta fibers). As used herein,the term “secondary neurogenic inflammation” refers to tissueinflammation initiated by non-neuronal sources (e.g., extravasation fromvascular bed or tissue interstitium-derived, such as from mast cells orimmune cells) of inflammatory mediators, such as peptides or cytokines,stimulating sensory nerve terminals and causing a release ofinflammatory mediators from the nerves. The net effect of both forms(primary and secondary) of chronic neurogenic inflammation is to have aninflammatory state that is maintained by the sensitization of theperipheral sensory nerve fibers. The physiological consequence of theresulting chronic neurogenic inflammation depends on the tissue inquestion, producing, such as, e.g., cutaneous pain (allodynia,hyperalgesia), joint pain and/or arthritis, visceral pain anddysfunction, pulmonary dysfunction, asthma, chronic obstructivepulmonary disease (COPD), and bladder dysfunction (e.g., pain,overactive bladder).

In some aspects, a pharmaceutical composition containing isomyosmine isadministered to an individual to treat a viral infection. In oneexample, the virus is human immunodeficiency virus (HIV). In anotherexample, the virus is herpes simplex virus (HSV). In yet anotherexample, the virus is human papillomavirus (HPV). Low-risk mucosal HPVssuch as HPV-6 and HPV-11 cause genital warts (condyloma accuminata),whereas the high-risk HPVs cause squamous intraepithelial lesions thatcan progress to invasive squamous cell carcinoma. The vast majority ofhuman cervical cancers are associated with high-risk HPV infections.HPV-16 is by far the most prevalent mucosal high-risk HPV type, followedby HPV-18 and HPV-31. Approximately 20% of oral cancers, particularlyoropharyngeal carcinomas in patients that lack the classical riskfactors of tobacco and alcohol abuse, are also high-risk HPV positive.Other anogenital tract malignancies that are also frequently associatedwith high-risk HPV infections include penile and vulvovaginal cancers aswell as anal carcinomas, which frequently occur in individuals withhuman immunodeficiency virus (HIV)-associated AIDS.

In one aspect, isomyosmine may be administered to individual to treathigh blood pressure (hypertension). Isomyosmine is believed to treatsymptoms of high blood pressure and hypertension by restoring normalfunction to cells in the bloodline.

A composition or compound as described herein may be administered to anindividual. An individual is typically a human being. Typically, anyindividual who is a candidate for a conventional chronic inflammationtreatment is a candidate for a chronic inflammation treatment disclosedherein. Pre-operative evaluation typically includes routine history andphysical examination in addition to thorough informed consent disclosingall relevant risks and benefits of the procedure.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in a therapeutically effective amount. As used herein, the term“effective amount” is synonymous with “therapeutically effectiveamount,” “effective dose,” or “therapeutically effective dose,” and whenused in reference to treating a chronic inflammation refers to theminimum dose of a therapeutic compound disclosed herein necessary toachieve the desired therapeutic effect and includes a dose sufficient toreduce a symptom associated with a chronic inflammation. Theeffectiveness of a therapeutic compound disclosed herein in treating achronic inflammation can be determined by observing an improvement in anindividual based upon one or more clinical symptoms, and/orphysiological indicators associated with the condition. An improvementin a chronic inflammation also can be indicated by a reduced need for aconcurrent therapy.

The appropriate effective amount of a therapeutic compound disclosedherein to be administered to an individual for a particular chronicinflammation can be determined by a person of ordinary skill in the artby taking into account factors, including, without limitation, the typeof chronic inflammation, the location of the chronic inflammation, thecause of the chronic inflammation, the severity of the chronicinflammation, the degree of relief desired, the duration of reliefdesired, the particular therapeutic compound used, the rate of excretionof the therapeutic compound used, the pharmacodynamics of thetherapeutic compound used, the nature of the other compounds to beincluded in the composition, the particular route of administration, theparticular characteristics, history and risk factors of the patient,such as, e.g., age, weight, general health and the like, or anycombination thereof. Additionally, where repeated administration of atherapeutic compound is used, an effective amount of a therapeuticcompound will further depend upon factors, including, withoutlimitation, the frequency of administration, the half-life of thetherapeutic compound, or any combination thereof. In is known by aperson of ordinary skill in the art that an effective amount of atherapeutic compound disclosed herein can be extrapolated from in vitroassays and in vivo administration studies using animal models prior toadministration to humans.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein reduces a symptom associated witha chronic inflammation by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95% or at least 100%. In other aspects of this embodiment, atherapeutically effective amount of a therapeutic compound disclosedherein reduces a symptom associated with a chronic inflammation by,e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%,at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, atmost 90%, at most 95% or at most 100%. In yet other aspects of thisembodiment, a therapeutically effective amount of a therapeutic compounddisclosed herein reduces a symptom associated with a chronicinflammation by, e.g., about 10% to about 100%, about 10% to about 90%,about 10% to about 80%, about 10% to about 70%, about 10% to about 60%,about 10% to about 50%, about 10% to about 40%, about 20% to about 100%,about 20% to about 90%, about 20% to about 80%, about 20% to about 20%,about 20% to about 60%, about 20% to about 50%, about 20% to about 40%,about 30% to about 100%, about 30% to about 90%, about 30% to about 80%,about 30% to about 70%, about 30% to about 60%, or about 30% to about50%.

In yet other aspects of this embodiment, a therapeutically effectiveamount of a therapeutic compound disclosed herein generally is in therange of about 0.001 mg/kg/day to about 100 mg/kg/day. In aspects ofthis embodiment, an effective amount of a therapeutic compound disclosedherein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day,at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day,at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, atleast 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, atleast 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. Inother aspects of this embodiment, an effective amount of a therapeuticcompound disclosed herein may be in the range of, e.g., about 0.001mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100mg/kg/day. In yet other aspects of this embodiment, an effective amountof a therapeutic compound disclosed herein may be in the range of, e.g.,about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day toabout 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100mg/kg/day. In still other aspects of this embodiment, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/dayto about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be in the range of, e.g.,about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 5 mg/kg/day to about 10mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day toabout 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day toabout 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100mg/kg/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa chronic inflammation may comprise a one-time administration of aneffective dose of a pharmaceutical composition disclosed herein.Alternatively, treatment of a chronic inflammation may comprise multipleadministrations of an effective dose of a pharmaceutical compositioncarried out over a range of time periods, such as, e.g., once daily,twice daily, trice daily, once every few days, or once weekly. Thetiming of administration can vary from individual to individual,depending upon such factors as the severity of an individual's symptoms.For example, an effective dose of a pharmaceutical composition disclosedherein can be administered to an individual once daily for an indefiniteperiod of time, or until the individual no longer requires therapy. Aperson of ordinary skill in the art will recognize that the condition ofthe individual can be monitored throughout the course of treatment andthat the effective amount of a pharmaceutical composition disclosedherein that is administered can be adjusted accordingly.

In one embodiment, upon administration to an individual, apharmaceutical composition comprising a therapeutic compound disclosedherein results in a bio-distribution of the therapeutic compounddifferent than a bio-distribution of the therapeutic compound includedin the same pharmaceutical composition, except without an adjuvantdisclosed herein.

In another embodiment, upon administration to an individual, atherapeutic compound of the pharmaceutical composition disclosed hereinis delivered to a macrophage. Macrophages are one of the key cell typesbelieved to be involved in the control of the inflammation response. Theresultant high level of a therapeutic compound having anti-inflammatoryactivity present in the macrophages results in a clinically effectivetreatment of chronic inflammation. In an aspect of this embodiment, uponadministration to an individual, a therapeutically effective amount of atherapeutic compound of the pharmaceutical composition disclosed hereinis preferentially delivered to a macrophage. In other aspect of thisembodiment, upon administration to an individual, a therapeutic compoundof the pharmaceutical composition disclosed herein is substantiallydelivered to a macrophage. In yet other aspect of this embodiment, uponadministration to an individual, the amount of a therapeutic compound ofthe pharmaceutical composition disclosed herein delivered to amacrophage is, e.g., at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or at least 100% of the total amount of the therapeutic compoundcontained in the administered pharmaceutical composition. In still otheraspects of this embodiment, upon administration to an individual, theamount of a therapeutic compound of the pharmaceutical compositiondisclosed herein delivered to a macrophage is in a range of, e.g., about5% to about 100%, about 10% to about 100%, about 15% to about 100%,about 20% to about 100%, about 25% to about 100%, about 30% to about100%, about 35% to about 100%, about 40% to about 100%, about 45% toabout 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% toabout 90%, about 30% to about 90%, about 35% to about 90%, about 40% toabout 90%, about 45% to about 90%, about 50% to about 90%, about 5% toabout 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% toabout 80%, about 40% to about 80%, about 45% to about 80%, about 50% toabout 80%, about 5% to about 70%, about 10% to about 70%, about 15% toabout 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 70%, about 35% to about 70%, about 40% to about 70%, about 45% toabout 70%, or about 50% to about 70% of the total amount of thetherapeutic compound contained in the administered pharmaceuticalcomposition.

In another embodiment, upon administration to an individual, apharmaceutical composition disclosed herein reduces gastric irritation.In an aspect of this embodiment, a pharmaceutical composition disclosedherein substantially reduces gastric irritation. In yet anotherembodiment, upon administration to an individual, a pharmaceuticalcomposition disclosed herein reduces gastric irritation when compared tothe same pharmaceutical composition disclosed herein, except without thepharmaceutically acceptable adjuvant. In an aspect of this embodiment, apharmaceutical composition disclosed herein substantially reducesgastric irritation when compared to the same pharmaceutical compositiondisclosed herein, except without the pharmaceutically acceptableadjuvant. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein reduces gastric irritation by, e.g., atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, or at least 100%.In yet other aspects of this embodiment, a pharmaceutical compositiondisclosed herein reduces gastric irritation in a range of, e.g., about5% to about 100%, about 10% to about 100%, about 15% to about 100%,about 20% to about 100%, about 25% to about 100%, about 30% to about100%, about 35% to about 100%, about 40% to about 100%, about 45% toabout 100%, about 50% to about 100%, about 5% to about 90%, about 10% toabout 90%, about 15% to about 90%, about 20% to about 90%, about 25% toabout 90%, about 30% to about 90%, about 35% to about 90%, about 40% toabout 90%, about 45% to about 90%, about 50% to about 90%, about 5% toabout 80%, about 10% to about 80%, about 15% to about 80%, about 20% toabout 80%, about 25% to about 80%, about 30% to about 80%, about 35% toabout 80%, about 40% to about 80%, about 45% to about 80%, about 50% toabout 80%, about 5% to about 70%, about 10% to about 70%, about 15% toabout 70%, about 20% to about 70%, about 25% to about 70%, about 30% toabout 70%, about 35% to about 70%, about 40% to about 70%, about 45% toabout 70%, or about 50% to about 70%.

In another embodiment, upon administration to an individual, apharmaceutical composition reduces intestinal irritation. In an aspectof this embodiment, a pharmaceutical composition substantially reducesintestinal irritation. In yet another embodiment, upon administration toan individual, a pharmaceutical composition disclosed herein reducesintestinal irritation when compared to the same pharmaceuticalcomposition disclosed herein, except without the pharmaceuticallyacceptable adjuvant. In an aspect of this embodiment, a pharmaceuticalcomposition disclosed herein substantially reduces intestinal irritationwhen compared to the same pharmaceutical composition disclosed herein,except without the pharmaceutically acceptable adjuvant. In otheraspects of this embodiment, a pharmaceutical composition disclosedherein reduces intestinal irritation by, e.g., at least 5%, at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, or at least 100% whencompared to the same pharmaceutical composition disclosed herein, exceptwithout the pharmaceutically acceptable adjuvant. In yet other aspectsof this embodiment, a pharmaceutical composition disclosed hereinreduces intestinal irritation by, e.g., about 5% to about 100%, about10% to about 100%, about 15% to about 100%, about 20% to about 100%,about 25% to about 100%, about 30% to about 100%, about 35% to about100%, about 40% to about 100%, about 45% to about 100%, about 50% toabout 100%, about 5% to about 90%, about 10% to about 90%, about 15% toabout 90%, about 20% to about 90%, about 25% to about 90%, about 30% toabout 90%, about 35% to about 90%, about 40% to about 90%, about 45% toabout 90%, about 50% to about 90%, about 5% to about 80%, about 10% toabout 80%, about 15% to about 80%, about 20% to about 80%, about 25% toabout 80%, about 30% to about 80%, about 35% to about 80%, about 40% toabout 80%, about 45% to about 80%, about 50% to about 80%, about 5% toabout 70%, about 10% to about 70%, about 15% to about 70%, about 20% toabout 70%, about 25% to about 70%, about 30% to about 70%, about 35% toabout 70%, about 40% to about 70%, about 45% to about 70%, or about 50%to about 70% when compared to the same pharmaceutical compositiondisclosed herein, except without the pharmaceutically acceptableadjuvant.

A pharmaceutical composition disclosed herein can also be administeredto an individual in combination with other therapeutic compounds toincrease the overall therapeutic effect of the treatment. The use ofmultiple compounds to treat an indication can increase the beneficialeffects while reducing the presence of side effects.

The following examples illustrate but do not limit the scope of thedisclosure set forth above.

EXAMPLE 1

This example describes experiments for determining monoamine oxidase(MAO) inhibition for isomyosmine and other alkaloids. MAOs are enzymeslocated on the outer membrane of mitochondria and are involved in thecatabolism of monoamine neurotransmitters. There are twowell-characterized isoenzymes: MAO-A, which predominantly catabolizesserotonin and norepinephrine, and MAO-B, which preferentiallycatabolizes benzylamine and phenylethylamine. Dopamine and tyramine aremetabolized by both isoforms.

To detect the activity of MAO, a luminescent method (MAO-Glo Assay kit,from Promega, Cat # V1401) was used. In this method, a MAO substrate (aderivative of beetle luciferin provided in the kit) is mixed with thecompound to be tested (in this case, myosmine and control compounds).Then, the MAO enzymes (either A or B, purchased separately) are added tothe mixture and incubated with the reaction for 1 hour at roomtemperature. The MAO enzymes, if not inhibited by the test compound,will convert the substrate into methyl ester luciferin. Finally, aluciferin detection reagent (provided by the kit) is added (20 minutesat room temperature) to stop the MAO reaction and convert methyl esterluciferin into D-luciferin. D-luciferin reacts with luciferase toproduce a luminescent signal, which is directly proportional to theD-luciferin concentration and thus the MAO activity: the greater theamount of light produced the higher the activity of MAO. The luminescentsignal is measured and recorded using a luminometer.

The following materials were obtained from Toronto Research Chemicals,North York, ON: isomyosmine, catalog # I821350; myosmine, catalog #M835000; anabasine, catalog # A637175; and nornicotine, catalog #N756995. Anatabine was obtained from Emerson Resources, Norristown, Pa.

As positive controls for the experiment, clorgyline (awell-characterized potent inhibitor of MAO-A) and deprenyl (awell-characterized potent inhibitor of MAO-B) were used.

Results for MAO-A activity

When the pure alkaloids isomyosmine, myosmine, anatabine, anabasine, andnornicotine were compared, isomyosmine was the most potent of the fivein inhibiting the enzymatic activity of MAO-A (FIG. 1). The way to readthis line graph is the following: a 100% activity means that the testcompound has no effect on the enzyme; a 0% activity means that the testcompound completely kills the enzyme. The more the curve is shifted tothe left, the greater the inhibition the test compound exerts on theenzyme. As can be seen in FIG. 1, the curve for isomyosmine is moreshifted to the left among the five alkaloids tested. A 2 mMconcentration (2,000 micromolar) gives an inhibition of about 50%. Thecurve for clorgyline, the positive control for the experiment, isgreatly shifted leftward.

Results for MAO-B activity

Similar results were obtained when testing the five pure alkaloidsisomyosmine, myosmine, anatabine, anabasine, and nornicotine for theinhibition of MAO-B. Isomyosmine was the most potent among the fivealkaloids tested at inhibiting the activity of MAO-B (FIG. 2).

EXAMPLE 2

This example illustrates treating a stage-four cancer patient who hadbeen diagnosed with autoimmune amyloidosis. At the time treatment began,the individual was bedridden under hospice care and told he had only afew days to live. The individual was administered a daily dose of 250 mgisomyosmine. Within two weeks of treatment, the individual's symptomshad remarkably improved and the individual was able to get out of bedand walk around.

The patient's blood was tested using conventional immunoglobulin lightchain Kappa/Lambda detection. The immunoglobulin kappa and lambda (Igκ/λ) in situ hybridization (ISH) system is designed for the detection ofhuman kappa and lambda immunoglobulin light chain messenger RNA (mRNA)in tissue sections and blood and bone marrow smears. The system usesbiotin-labeled oligonucleotide probes. The probe-mRNA duplex isindirectly detected using an enzyme-conjugated antibody targeting thebiotin conjugate. For color development, a chromogenic substrate isadded. Enzymatic reaction of the chromogenic substrate leads to theformation of a color precipitate that is visualized by light microscopy.Results are shown in Table 1 below.

TABLE 1 Test 3 9 12 14 17 standard range Initial weeks weeks weeks weeksweeks Free Light 75.38 55.23 42.83 29.58 64.33 28.89 Chains Ratio 0.26□1.65 Kappa Light 490.0 602.0 394.0 210.0 193.0 104.0 Chains 3.3 □19.4mg/L Lambda Light 6.5 10.9 9.2 7.1 3.0 3.6 Chains 5.7 □26.3 mg/L

EXAMPLE 3

This example illustrates administering isomyosmine to treat herpeslabialis (cold sores), a type of herpes simplex occurring on the lip. Anindividual who experiences periodic outbreaks of herpes labialis wasadministered a 100 mg dose of isomyosmine upon first feeling the onsetof a cold sore. The treatment was effective to prevent the outbreak ofthe cold sore.

EXAMPLE 4

This example illustrates administering isomyosmine to treat high bloodpressure. Twelve individuals experiencing high blood pressure were eachadministered isomyosmine at dose of 100 mg per day. Each of theindividuals experienced a reduction in blood pressure during the courseof treatment. The blood pressure of one of the individuals was measuredto be 145/86 mmHg without isomyosmine in the bloodstream and wasmeasured to be 109/59 mmHg while being treated with isomyosmine. Anotherof the individuals was being treated for type II diabetes at thebeginning of the treatment. Following three months of treatment, theindividual showed no symptoms of diabetes and was taken off his existingdiabetes medication.

While particular embodiments have been described and illustrated, itshould be understood that the invention is not limited thereto sincemodifications may be made by persons skilled in the art. The presentapplication contemplates any and all modifications that fall within thespirit and scope of the underlying invention disclosed and claimedherein.

What is claimed is:
 1. A method of treating a viral infection comprisingadministering to an individual in need thereof a pharmaceuticalcomposition containing a therapeutically effective amount of isomyosmineor a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the viral infection is human immunodeficiency virus (HIV). 3.The method of claim 1, wherein the viral infection is humanpapillomavirus (HPV).
 4. The method of claim 1, wherein the viralinfection is herpes simplex virus (HSV).
 5. The method of claim 1,wherein the therapeutically effective amount is from about 0.01 to about50 mg/kg/day.
 6. The method of claim 1, wherein the therapeuticallyeffective amount is from about 0.1 to about 25 mg/kg/day.
 7. The methodof claim 1, wherein the therapeutically effective amount is from about 1to about 10 mg/kg/day.
 8. The method of claim 1, wherein thepharmaceutically acceptable salt is isomyosmine hydrochloride.
 9. Amethod of treating influenza comprising administering to an individualin need thereof a pharmaceutical composition containing atherapeutically effective amount of isomyosmine or a pharmaceuticallyacceptable salt thereof.
 10. The method of claim 9, wherein thetherapeutically effective amount is from about 0.01 to about 50mg/kg/day.
 11. The method of claim 9, wherein the therapeuticallyeffective amount is from about 0.1 to about 25 mg/kg/day.
 12. The methodof claim 9, wherein the therapeutically effective amount is from about 1to about 10 mg/kg/day.
 13. The method of claim 9, wherein thepharmaceutically acceptable salt is isomyosmine hydrochloride.
 14. Amethod of inhibiting reactive oxygen species (ROS) in an individualsuffering from a viral infection comprising administering to theindividual a pharmaceutical composition containing a therapeuticallyeffective amount of isomyosmine or a pharmaceutically acceptable saltthereof.
 15. The method of claim 14, wherein the viral infection isinfluenza.
 16. The method of claim 14, wherein the viral infection ishuman immunodeficiency virus (HIV).
 17. The method of claim 14, whereinthe viral infection is herpes simplex virus (HSV).
 18. The method ofclaim 14, wherein the viral infection is human papillomavirus (HPV). 19.The method of claim 18, wherein the viral infection is HPV-16.
 20. Themethod of claim 18, wherein the viral infection is HPV-18 or HPV-31.